Drug Resistance Against Tyrosine Kinase Inhibitor in Gastrointestinal Malignancies

  • L. V. K. S. Bhaskar
  • L. Saikrishna


Gastrointestinal cancers are heterogeneous and complex among the most common human cancers. In spite of this complexity, certain types of genetic alterations are linked to specific pathological lesions. Genomic and transcriptomic analyses have disclosed molecular subtypes that are characterized by specific genetic aberrations and expression signatures. Identification of better molecular markers to assist detection and prognostic evaluation of the cancer is therefore required. Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades. Inhibitors of tyrosine kinases (TKIs) have been effectively used for clinical treatment of certain types of cancer. Chronic exposure to gradually increasing concentrations of the TKI over a period of time, cells by activating modified signaling pathway can replace the lack of signal in target therapy, leading to the development of drug resistance. In recent years, researchers have specified different subsets of tyrosine kinase inhibitors’ potential resistance mechanisms in various gastric cancers. This chapter intends to provide an overview of the most recently identified molecular mechanisms of acquired resistance to tyrosine kinase-targeted therapy in various gastrointestinal malignancies.


Gastrointestinal cancer Tyrosine kinase inhibitors TKI resistance EGFR VEGF HER2 



ATP binding cassette


Adenosine triphosphate


B-cell lymphoma 2


Basic fibroblast growth factor


Chronic myeloid leukemia


Epidermal growth factor receptor


Epithelial-mesenchymal transition


Epidermal growth factor receptor II (Her 2)


Extracellular signal-regulated kinase


Fibroblast growth factor receptor


Fluorescent in situ hybridization


FMS-like tyrosine kinase 3


Folinic acid (FA)-fluorouracil (5FU)-oxaliplatin (OX)


Gastric cancer




Gastroesophageal junction


Hepatocellular carcinoma


Hepatocyte growth factor


Human organic cation transporter type 1


Insulin receptor


Janus kinase


Monoclonal antibodies


Metastatic colorectal cancer


Mesenchymal-epithelial transition


Metastatic pancreatic cancer


Non-receptor tyrosine kinases


Overall survival


Platelet-derived growth factor receptors


Progression-free survival


Phosphatidylinositol 3-kinase catalytic subunit


Peroxisome proliferator-activated receptor delta


Phosphatase and TENsin homolog deleted on chromosome 10


Receptor tyrosine kinases


Transforming growth factor α


Tyrosine kinase inhibitor


Tyrosine kinases


Melting temperature


Vascular endothelial growth factor


Vascular endothelial growth factor receptors


  1. 1.
    Myint ZW, Goel G (2017) Role of modern immunotherapy in gastrointestinal malignancies: a review of current clinical progress. J Hematol Oncol 10:86PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Ramzi NH, Chahil JK, Lye SH et al (2014) Role of genetic & environment risk factors in the aetiology of colorectal cancer in Malaysia. Indian J Med Res 139:873–882PubMedPubMedCentralGoogle Scholar
  3. 3.
    Schlessinger J (2000) Cell signaling by receptor tyrosine kinases. Cell 103:211–225CrossRefGoogle Scholar
  4. 4.
    Mahajan K, Mahajan NP (2015) Cross talk of tyrosine kinases with the DNA damage signaling pathways. Nucleic Acids Res 43:10588–10601PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Gocek E, Moulas AN, Studzinski GP (2014) Non-receptor protein tyrosine kinases signaling pathways in normal and cancer cells. Crit Rev Clin Lab Sci 51:125–137PubMedCrossRefGoogle Scholar
  6. 6.
    Paul MK, Mukhopadhyay AK (2004) Tyrosine kinase–role and significance in cancer. Int J Med Sci 1:101–115PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Krause DS, Van Etten RA (2005) Tyrosine kinases as targets for cancer therapy. N Engl J Med 353:172–187PubMedCrossRefGoogle Scholar
  8. 8.
    Chen H, Boiziau J, Parker F et al (1994) Structure-activity relationships in a series of 5-[(2,5-dihydroxybenzyl)amino]salicylate inhibitors of EGF-receptor-associated tyrosine kinase: importance of additional hydrophobic aromatic interactions. J Med Chem 37:845–859PubMedCrossRefGoogle Scholar
  9. 9.
    Corn PG, Song DY, Heath E et al (2013) Sunitinib plus androgen deprivation and radiation therapy for patients with localized high-risk prostate cancer: results from a multi-institutional phase 1 study. Int J Radiat Oncol Biol Phys 86:540–545PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Tong CC, Ko EC, Sung MW et al (2012) Phase II trial of concurrent sunitinib and image-guided radiotherapy for oligometastases. PLoS One 7:e36979PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Wuthrick EJ, Kamrava M, Curran WJ Jr et al (2011) A phase 1b trial of the combination of the antiangiogenic agent sunitinib and radiation therapy for patients with primary and metastatic central nervous system malignancies. Cancer 117:5548–5559PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Liu Y, Gray NS (2006) Rational design of inhibitors that bind to inactive kinase conformations. Nat Chem Biol 2:358–364PubMedCrossRefGoogle Scholar
  13. 13.
    Knight ZA, Gonzalez B, Feldman ME et al (2006) A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell 125:733–747PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Ohren JF, Chen H, Pavlovsky A et al (2004) Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition. Nat Struct Mol Biol 11:1192–1197PubMedCrossRefGoogle Scholar
  15. 15.
    Kwak EL, Sordella R, Bell DW et al (2005) Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc Natl Acad Sci U S A 102:7665–7670PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Bain J, Plater L, Elliott M et al (2007) The selectivity of protein kinase inhibitors: a further update. Biochem J 408:297–315PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Fabian MA, Biggs Iii WH, Treiber DK et al (2005) A small molecule–kinase interaction map for clinical kinase inhibitors. Nat Biotechnol 23:329PubMedCrossRefGoogle Scholar
  18. 18.
    Fedorov O, Marsden B, Pogacic V et al (2007) A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases. Proc Natl Acad Sci U S A 104:20523–20528PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Warmuth M, Kim S, Gu XJ, Xia G, Adrian F (2007) Ba/F3 cells and their use in kinase drug discovery. Curr Opin Oncol 19:55–60PubMedCrossRefGoogle Scholar
  20. 20.
    Josephs DH, Fisher DS, Spicer J, Flanagan RJ (2013) Clinical pharmacokinetics of tyrosine kinase inhibitors: implications for therapeutic drug monitoring. Ther Drug Monit 35:562–587PubMedGoogle Scholar
  21. 21.
    Barouch-Bentov R, Sauer K (2011) Mechanisms of drug resistance in kinases. Expert Opin Investig Drugs 20:153–208PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Zahreddine H, Borden KL (2013) Mechanisms and insights into drug resistance in cancer. Front Pharmacol 4:28PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Dohse M, Scharenberg C, Shukla S et al (2010) Comparison of ATP-binding cassette transporter interactions with the tyrosine kinase inhibitors imatinib, nilotinib, and dasatinib. Drug Metab Dispos 38:1371–1380PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Tanaka R, Kimura S (2008) Abl tyrosine kinase inhibitors for overriding Bcr-Abl/T315I: from the second to third generation. Expert Rev Anticancer Ther 8:1387–1398PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Kreuzer KA, Le Coutre P, Landt O et al (2003) Preexistence and evolution of imatinib mesylate-resistant clones in chronic myelogenous leukemia detected by a PNA-based PCR clamping technique. Ann Hematol 82:284–289PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Ricci C, Scappini B, Divoky V et al (2002) Mutation in the ATP-binding pocket of the ABL kinase domain in an STI571-resistant BCR/ABL-positive cell line. Cancer Res 62:5995–5998PubMedPubMedCentralGoogle Scholar
  27. 27.
    Corso S, Ghiso E, Cepero V et al (2010) Activation of HER family members in gastric carcinoma cells mediates resistance to MET inhibition. Mol Cancer 9:121PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Sequist LV, Waltman BA, Dias-Santagata D et al (2011) Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 3:75ra26PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Suda K, Murakami I, Katayama T et al (2010) Reciprocal and complementary role of MET amplification and EGFR T790M mutation in acquired resistance to kinase inhibitors in lung cancer. Clin Cancer Res 16:5489–5498PubMedCrossRefGoogle Scholar
  30. 30.
    Engelman JA, Zejnullahu K, Mitsudomi T et al (2007) MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 316:1039–1043PubMedCrossRefGoogle Scholar
  31. 31.
    Turke AB, Zejnullahu K, Wu YL et al (2010) Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell 17:77–88PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Mahadevan D, Cooke L, Riley C et al (2007) A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors. Oncogene 26:3909–3919PubMedCrossRefGoogle Scholar
  33. 33.
    Bae SY, Hong JY, Lee HJ, Park HJ, Lee SK (2015) Targeting the degradation of AXL receptor tyrosine kinase to overcome resistance in gefitinib-resistant non-small cell lung cancer. Oncotarget 6:10146–10160PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Ben Hassine I, Gharbi H, Soltani I et al (2017) hOCT1 gene expression predict for optimal response to Imatinib in Tunisian patients with chronic myeloid leukemia. Cancer Chemother Pharmacol 79:737–745PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Bhamidipati PK, Kantarjian H, Cortes J, Cornelison AM, Jabbour E (2013) Management of imatinib-resistant patients with chronic myeloid leukemia. Ther Adv Hematol 4:103–117PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Jabbour E, Deininger M, Hochhaus A (2011) Management of adverse events associated with tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia. Leukemia 25:201–210PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Cohen MH, Dagher R, Griebel DJ et al (2002) U.S. Food and Drug Administration drug approval summaries: imatinib mesylate, mesna tablets, and zoledronic acid. Oncologist 7:393–400PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Dagher R, Cohen M, Williams G et al (2002) Approval summary: imatinib mesylate in the treatment of metastatic and/or unresectable malignant gastrointestinal stromal tumors. Clin Cancer Res 8:3034–3038PubMedGoogle Scholar
  39. 39.
    Gravalos C, Grande E, Gasent JM (2010) The potential role of sunitinib in gastrointestinal cancers other than GIST. Crit Rev Oncol Hematol 76:36–43PubMedCrossRefGoogle Scholar
  40. 40.
    Grothey A, Van Cutsem E, Sobrero A et al (2013) Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet (London, England) 381:303–312CrossRefGoogle Scholar
  41. 41.
    Li J, Qin S, Xu R et al (2015) Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 16:619–629PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    D’Angelo S, Germano D, Zolfino T et al (2015) Therapeutic decisions and treatment with sorafenib in hepatocellular carcinoma: final analysis of GIDEON study in Italy. Recenti Prog Med 106:217–226PubMedGoogle Scholar
  43. 43.
    Moore MJ, Goldstein D, Hamm J et al (2007) Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25:1960–1966CrossRefGoogle Scholar
  44. 44.
    Carvalho TI, Novais PC, Lizarte FSN et al (2017) Analysis of gene expression EGFR and KRAS, microRNA-21 and microRNA-203 in patients with colon and rectal cancer and correlation with clinical outcome and prognostic factors. Acta Cir Bras 32:243–250PubMedCrossRefGoogle Scholar
  45. 45.
    Ooi A, Takehana T, Li X et al (2004) Protein overexpression and gene amplification of HER-2 and EGFR in colorectal cancers: an immunohistochemical and fluorescent in situ hybridization study. Mod Pathol 17:895–904PubMedCrossRefGoogle Scholar
  46. 46.
    Favoni RE, Pattarozzi A, Lo Casto M et al (2010) Gefitinib targets EGFR dimerization and ERK1/2 phosphorylation to inhibit pleural mesothelioma cell proliferation. Curr Cancer Drug Targets 10:176–191PubMedCrossRefGoogle Scholar
  47. 47.
    Knickelbein K, Zhang L (2015) Mutant KRAS as a critical determinant of the therapeutic response of colorectal cancer. Genes Dis 2:4–12PubMedCrossRefGoogle Scholar
  48. 48.
    Yazdi MH, Faramarzi MA, Nikfar S, Abdollahi MA (2015) Comprehensive review of clinical trials on EGFR inhibitors such as cetuximab and panitumumab as monotherapy and in combination for treatment of metastatic colorectal cancer. Avicenna J Med Biotechnol 7:134–144PubMedPubMedCentralGoogle Scholar
  49. 49.
    Niu G, Chen X (2010) Vascular endothelial growth factor as an anti-angiogenic target for cancer therapy. Curr Drug Targets 11:1000–1017PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Ferrara N, Hillan KJ, Novotny W (2005) Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy. Biochem Biophys Res Commun 333:328–335PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Tol J, Punt CJ (2010) Monoclonal antibodies in the treatment of metastatic colorectal cancer: a review. Clin Ther 32:437–453PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Tew WP, Gordon M, Murren J et al (2010) Phase 1 study of aflibercept administered subcutaneously to patients with advanced solid tumors. Clin Cancer Res 16:358–366PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Syed YY, McKeage K (2015) Aflibercept: a review in metastatic colorectal cancer. Drugs 75:1435–1445PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Ruff P, Van Cutsem E, Lakomy R, et al (2018) Observed benefit and safety of aflibercept in elderly patients with metastatic colorectal cancer: an age-based analysis from the randomized placebo-controlled phase III VELOUR trial. J Geriatr Oncol 9(1):32–39PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Rosenberg DW, Yang S, Pleau DC et al (2007) Mutations in BRAF and KRAS differentially distinguish serrated versus non-serrated hyperplastic aberrant crypt foci in humans. Cancer Res 67:3551–3554PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Rajagopalan H, Bardelli A, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE (2002) Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature 418:934PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Bamford S, Dawson E, Forbes S et al (2004) The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website. Br J Cancer 91:355–358PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Wan PT, Garnett MJ, Roe SM et al (2004) Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 116:855–867PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    De Mattia E, Cecchin E, Toffoli G (2015) Pharmacogenomics of intrinsic and acquired pharmacoresistance in colorectal cancer: toward targeted personalized therapy. Drug Resist Updat 20:39–70PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Ong FS, Das K, Wang J et al (2012) Personalized medicine and pharmacogenetic biomarkers: progress in molecular oncology testing. Expert Rev Mol Diagn 12:593–602PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Lea A, Allingham-Hawkins D, Levine S (2010) BRAF p.Val600Glu (V600E) testing for assessment of treatment options in metastatic colorectal cancer. PLoS Curr 2:RRN1187PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Di Nicolantonio F, Martini M, Molinari F et al (2008) Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol 26:5705–5712PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Saridaki Z, Tzardi M, Sfakianaki M et al (2013) BRAFV600E mutation analysis in patients with metastatic colorectal cancer (mCRC) in daily clinical practice: correlations with clinical characteristics, and its impact on patients’ outcome. PLoS One 8:e84604PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Cremolini C, Di Bartolomeo M, Amatu A et al (2015) BRAF codons 594 and 596 mutations identify a new molecular subtype of metastatic colorectal cancer at favorable prognosis. Ann Oncol 26:2092–2097PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Samuels Y, Wang Z, Bardelli A et al (2004) High frequency of mutations of the PIK3CA gene in human cancers. Science 304:554PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Karakas B, Bachman KE, Park BH (2006) Mutation of the PIK3CA oncogene in human cancers. Br J Cancer 94:455–459PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Stec R, Semeniuk-Wojtas A, Charkiewicz R et al (2015) Mutation of the PIK3CA gene as a prognostic factor in patients with colorectal cancer. Oncol Lett 10:1423–1429PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Mita H, Toyota M, Aoki F et al (2009) A novel method, digital genome scanning detects KRAS gene amplification in gastric cancers: involvement of overexpressed wild-type KRAS in downstream signaling and cancer cell growth. BMC Cancer 9:198PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Mekenkamp LJ, Tol J, Dijkstra JR et al (2012) Beyond KRAS mutation status: influence of KRAS copy number status and microRNAs on clinical outcome to cetuximab in metastatic colorectal cancer patients. BMC Cancer 12:292PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Valtorta E, Misale S, Sartore-Bianchi A et al (2013) KRAS gene amplification in colorectal cancer and impact on response to EGFR-targeted therapy. Int J Cancer 133:1259–1265PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Cancer Genome Atlas N (2012) Comprehensive molecular characterization of human colon and rectal cancer. Nature 487:330–337CrossRefGoogle Scholar
  72. 72.
    Goel A, Arnold CN, Niedzwiecki D et al (2004) Frequent inactivation of PTEN by promoter hypermethylation in microsatellite instability-high sporadic colorectal cancers. Cancer Res 64:3014–3021PubMedCrossRefGoogle Scholar
  73. 73.
    Molinari F, Frattini M (2013) Functions and regulation of the PTEN gene in colorectal cancer. Front Oncol 3:326PubMedGoogle Scholar
  74. 74.
    Hobor S, Van Emburgh BO, Crowley E, Misale S, Di Nicolantonio F, Bardelli A (2014) TGFalpha and amphiregulin paracrine network promotes resistance to EGFR blockade in colorectal cancer cells. Clin Cancer Res 20:6429–6438PubMedCrossRefGoogle Scholar
  75. 75.
    Rahbari NN, Kedrin D, Incio J et al (2016) Anti-VEGF therapy induces ECM remodeling and mechanical barriers to therapy in colorectal cancer liver metastases. Sci Transl Med 8:360ra135PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Schultz K, Fanburg BL, Beasley D (2006) Hypoxia and hypoxia-inducible factor-1alpha promote growth factor-induced proliferation of human vascular smooth muscle cells. Am J Physiol Heart Circ Physiol 290:H2528–H2534PubMedCrossRefGoogle Scholar
  77. 77.
    Shi YH, Bingle L, Gong LH, Wang YX, Corke KP, Fang WG (2007) Basic FGF augments hypoxia induced HIF-1-alpha expression and VEGF release in T47D breast cancer cells. Pathology 39:396–400PubMedCrossRefGoogle Scholar
  78. 78.
    Yang L, Xiao M, Li X, Tang YI, Wang Y-L (2016) Arginine ADP-ribosyltransferase 1 promotes angiogenesis in colorectal cancer via the PI3K/Akt pathway. Int J Mol Med 37:734–742PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Ibrahim S, Girault A, Ohresser M, et al (2018) Monoclonal antibodies targeting the IL-17/IL-17RA axis: an opportunity to improve the efficiency of anti-VEGF therapy in fighting metastatic colorectal cancer? Clin Color Cancer 17(1):e109–e113PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    McGlynn KA, London WT (2011) The global epidemiology of hepatocellular carcinoma: present and future. Clin Liver Dis 15:223–243 vii–xPubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Lencioni R, Marrero J, Venook A, Ye SL, Kudo M (2010) Design and rationale for the non-interventional global investigation of therapeutic DEcisions in hepatocellular carcinoma and of its treatment with sorafenib (GIDEON) study. Int J Clin Pract 64:1034–1041PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Kim S, Abou-Alfa GK (2014) The role of tyrosine kinase inhibitors in hepatocellular carcinoma. Clin Adv Hematol Oncol 12:36–41PubMedGoogle Scholar
  83. 83.
    von Felden J, Schulze K, Gil-Ibanez I, Werner T, Wege H (2016) First- and second-line targeted systemic therapy in hepatocellular carcinoma-an update on patient selection and response evaluation. Diagnostics (Basel) 6(4): pii: E44Google Scholar
  84. 84.
    Deng GL, Zeng S, Shen H (2015) Chemotherapy and target therapy for hepatocellular carcinoma: new advances and challenges. World J Hepatol 7:787–798PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Chu JS, Ge FJ, Zhang B et al (2013) Expression and prognostic value of VEGFR-2, PDGFR-beta, and c-Met in advanced hepatocellular carcinoma. J Exp Clin Cancer Res 32:16PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Xue F, Liu Y, Chu H et al (2016) eIF5A2 is an alternative pathway for cell proliferation in cetuximab-treated epithelial hepatocellular carcinoma. Am J Transl Res 8:4670–4681PubMedPubMedCentralGoogle Scholar
  87. 87.
    Niu L, Liu L, Yang S, Ren J, Lai PBS, Chen GG (2017) New insights into sorafenib resistance in hepatocellular carcinoma: responsible mechanisms and promising strategies. Biochim Biophys Acta 1868:564–570Google Scholar
  88. 88.
    Zhu YJ, Zheng B, Wang HY, Chen L (2017) New knowledge of the mechanisms of sorafenib resistance in liver cancer. Acta Pharmacol Sin 38:614–622PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Zhao H, Lv F, Liang G et al (2016) FGF19 promotes epithelial-mesenchymal transition in hepatocellular carcinoma cells by modulating the GSK3beta/beta- catenin signaling cascade via FGFR4 activation. Oncotarget 7:13575–13586PubMedPubMedCentralGoogle Scholar
  90. 90.
    Gao L, Wang X, Tang Y, Huang S, Hu CA, Teng Y (2017) FGF19/FGFR4 signaling contributes to the resistance of hepatocellular carcinoma to sorafenib. J Exp Clin Cancer Res 36:8PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Singh A, Settleman J (2010) EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 29:4741–4751PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Berasain C (2013) Hepatocellular carcinoma and sorafenib: too many resistance mechanisms? Gut 62:1674–1675PubMedCrossRefPubMedCentralGoogle Scholar
  93. 93.
    Ye L, Yang X, Guo E et al (2014) Sorafenib metabolism is significantly altered in the liver tumor tissue of hepatocellular carcinoma patient. PLoS One 9:e96664PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Edginton AN, Zimmerman EI, Vasilyeva A, Baker SD, Panetta JC (2016) Sorafenib metabolism, transport, and enterohepatic recycling: physiologically based modeling and simulation in mice. Cancer Chemother Pharmacol 77:1039–1052PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Kim MJ, Choi YK, Park SY et al (2017) PPARdelta reprograms glutamine metabolism in sorafenib-resistant HCC. Mol Cancer Res 15:1230–1242PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    Malvezzi M, Carioli G, Bertuccio P et al (2017) European cancer mortality predictions for the year 2017, with focus on lung cancer. Ann Oncol 28:1117–1123PubMedCrossRefPubMedCentralGoogle Scholar
  97. 97.
    Siegel RL, Miller KD, Jemal A (2016) Cancer statistics, 2016. CA Cancer J Clin 66:7–30PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Liao R, Yang J, Zhou BY et al (2015) Conditional survival of pancreatic ductal adenocarcinoma in surgical and nonsurgical patients: a retrospective analysis report from a single institution in China. World J Surg Oncol 13:196PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Andren-Sandberg A (2011) Pancreatic cancer: chemotherapy and radiotherapy. N Am J Med Sci 3:1–12PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Friess H, Wang L, Zhu Z et al (1999) Growth factor receptors are differentially expressed in cancers of the papilla of vater and pancreas. Ann Surg 230:767–774 discussion 774–765PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Durkin AJ, Osborne DA, Yeatman TJ, Rosemurgy AS, Armstrong C, Zervos EE (2006) EGF receptor antagonism improves survival in a murine model of pancreatic adenocarcinoma. J Surg Res 135:195–201PubMedCrossRefGoogle Scholar
  102. 102.
    Burris HA 3rd, Moore MJ, Andersen J et al (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15:2403–2413PubMedCrossRefGoogle Scholar
  103. 103.
    Burris H, Storniolo AM (1997) Assessing clinical benefit in the treatment of pancreas cancer: gemcitabine compared to 5-fluorouracil. Eur J Cancer 33(Suppl 1):S18–S22PubMedCrossRefGoogle Scholar
  104. 104.
    Renouf DJ, Tang PA, Hedley D et al (2014) A phase II study of erlotinib in gemcitabine refractory advanced pancreatic cancer. Eur J Cancer 50:1909–1915PubMedCrossRefGoogle Scholar
  105. 105.
    Hammel P, Huguet F, van Laethem JL et al (2016) Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: the LAP07 randomized clinical trial. JAMA 315:1844–1853PubMedCrossRefGoogle Scholar
  106. 106.
    Kindler HL, Friberg G, Singh DA et al (2005) Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol 23:8033–8040PubMedCrossRefGoogle Scholar
  107. 107.
    Ko AH, Dito E, Schillinger B et al (2008) A phase II study evaluating bevacizumab in combination with fixed-dose rate gemcitabine and low-dose cisplatin for metastatic pancreatic cancer: is an anti-VEGF strategy still applicable? Investig New Drugs 26:463–471CrossRefGoogle Scholar
  108. 108.
    Xiong HQ, Rosenberg A, LoBuglio A et al (2004) Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor, in combination with gemcitabine for advanced pancreatic cancer: a multicenter phase II trial. J Clin Oncol 22:2610–2616PubMedCrossRefGoogle Scholar
  109. 109.
    Wei D, Wang L, He Y, Xiong HQ, Abbruzzese JL, Xie K (2004) Celecoxib inhibits vascular endothelial growth factor expression in and reduces angiogenesis and metastasis of human pancreatic cancer via suppression of Sp1 transcription factor activity. Cancer Res 64:2030–2038PubMedCrossRefGoogle Scholar
  110. 110.
    Van Cutsem E, Vervenne WL, Bennouna J et al (2009) Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. J Clin Oncol 27:2231–2237PubMedCrossRefGoogle Scholar
  111. 111.
    Ko AH, Youssoufian H, Gurtler J et al (2012) A phase II randomized study of cetuximab and bevacizumab alone or in combination with gemcitabine as first-line therapy for metastatic pancreatic adenocarcinoma. Investig New Drugs 30:1597–1606CrossRefGoogle Scholar
  112. 112.
    Hu-Lowe DD, Zou HY, Grazzini ML et al (2008) Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3. Clin Cancer Res 14:7272–7283PubMedCrossRefPubMedCentralGoogle Scholar
  113. 113.
    Spano JP, Chodkiewicz C, Maurel J et al (2008) Efficacy of gemcitabine plus axitinib compared with gemcitabine alone in patients with advanced pancreatic cancer: an open-label randomised phase II study. Lancet (London, England) 371:2101–2108CrossRefGoogle Scholar
  114. 114.
    Kindler HL, Ioka T, Richel DJ et al (2011) Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. Lancet Oncol 12:256–262PubMedCrossRefGoogle Scholar
  115. 115.
    Bournet B, Buscail C, Muscari F, Cordelier P, Buscail L (2016) Targeting KRAS for diagnosis, prognosis, and treatment of pancreatic cancer: hopes and realities. Eur J Cancer 54:75–83PubMedCrossRefGoogle Scholar
  116. 116.
    Kim ST, Lim DH, Jang KT et al (2011) Impact of KRAS mutations on clinical outcomes in pancreatic cancer patients treated with first-line gemcitabine-based chemotherapy. Mol Cancer Ther 10:1993–1999PubMedCrossRefGoogle Scholar
  117. 117.
    Propper D, Davidenko I, Bridgewater J et al (2014) Phase II, randomized, biomarker identification trial (MARK) for erlotinib in patients with advanced pancreatic carcinoma. Ann Oncol 25:1384–1390PubMedCrossRefGoogle Scholar
  118. 118.
    Philip PA, Lutz MP (2015) Targeting epidermal growth factor receptor-related signaling pathways in pancreatic cancer. Pancreas 44:1046–1052PubMedCrossRefPubMedCentralGoogle Scholar
  119. 119.
    Yotsumoto F, Fukami T, Yagi H et al (2010) Amphiregulin regulates the activation of ERK and Akt through epidermal growth factor receptor and HER3 signals involved in the progression of pancreatic cancer. Cancer Sci 101:2351–2360PubMedCrossRefGoogle Scholar
  120. 120.
    Ioannou N, Seddon AM, Dalgleish A, Mackintosh D, Solca F, Modjtahedi H (2016) Acquired resistance of pancreatic cancer cells to treatment with gemcitabine and HER-inhibitors is accompanied by increased sensitivity to STAT3 inhibition. Int J Oncol 48:908–918PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Huang C, Cao J, Huang KJ et al (2006) Inhibition of STAT3 activity with AG490 decreases the invasion of human pancreatic cancer cells in vitro. Cancer Sci 97:1417–1423PubMedCrossRefGoogle Scholar
  122. 122.
    Hudson CD, Hagemann T, Mather SJ, Avril N (2014) Resistance to the tyrosine kinase inhibitor axitinib is associated with increased glucose metabolism in pancreatic adenocarcinoma. Cell Death Dis 5:e1160PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Feig C, Gopinathan A, Neesse A, Chan DS, Cook N, Tuveson DA (2012) The pancreas cancer microenvironment. Clin Cancer Res 18:4266–4276PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Provenzano PP, Cuevas C, Chang AE, Goel VK, Von Hoff DD, Hingorani SR (2012) Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 21:418–429PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Duan JX, Jiao H, Kaizerman J et al (2008) Potent and highly selective hypoxia-activated achiral phosphoramidate mustards as anticancer drugs. J Med Chem 51:2412–2420PubMedCrossRefGoogle Scholar
  126. 126.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90PubMedCrossRefGoogle Scholar
  127. 127.
    Nagatsuma AK, Aizawa M, Kuwata T et al (2015) Expression profiles of HER2, EGFR, MET and FGFR2 in a large cohort of patients with gastric adenocarcinoma. Gastric Cancer 18:227–238PubMedCrossRefGoogle Scholar
  128. 128.
    Bang YJ, Van Cutsem E, Feyereislova A et al (2010) Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet (London, England) 376:687–697CrossRefGoogle Scholar
  129. 129.
    Won E, Janjigian YJ, Ilson DH (2014) HER2 directed therapy for gastric/esophageal cancers. Curr Treat Options Oncol 15:395–404PubMedCrossRefGoogle Scholar
  130. 130.
    Kang YK, Rha SY, Tassone P et al (2014) A phase IIa dose-finding and safety study of first-line pertuzumab in combination with trastuzumab, capecitabine and cisplatin in patients with HER2-positive advanced gastric cancer. Br J Cancer 111:660–666PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Hecht JR, Bang YJ, Qin SK et al (2016) Lapatinib in combination with capecitabine plus oxaliplatin in human epidermal growth factor receptor 2-positive advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma: TRIO-013/LOGiC – a randomized phase III trial. J Clin Oncol 34:443–451PubMedCrossRefGoogle Scholar
  132. 132.
    Han S, Meng Y, Tong Q et al (2014) The ErbB2-targeting antibody trastuzumab and the small-molecule SRC inhibitor saracatinib synergistically inhibit ErbB2-overexpressing gastric cancer. MAbs 6:403–408PubMedCrossRefGoogle Scholar
  133. 133.
    Zhang L, Yang J, Cai J et al (2013) A subset of gastric cancers with EGFR amplification and overexpression respond to cetuximab therapy. Sci Rep 3:2992PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Lordick F, Kang YK, Chung HC et al (2013) Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial. Lancet Oncol 14:490–499PubMedCrossRefGoogle Scholar
  135. 135.
    Waddell T, Chau I, Cunningham D et al (2013) Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial. Lancet Oncol 14:481–489PubMedPubMedCentralCrossRefGoogle Scholar
  136. 136.
    Xu CD (2014) Clinical study of nimotuzumab combined with chemotherapy in the treatment of late stage gastric cancer. Asian Pac J Cancer Prev 15:10273–10276PubMedCrossRefGoogle Scholar
  137. 137.
    Kishida O, Miyazaki Y, Murayama Y et al (2005) Gefitinib (“Iressa”, ZD1839) inhibits SN38-triggered EGF signals and IL-8 production in gastric cancer cells. Cancer Chemother Pharmacol 55:393–403PubMedCrossRefGoogle Scholar
  138. 138.
    Kishida O, Miyazaki Y, Murayama Y et al (2005) Gefitinib (Iressa, ZD1839) inhibits SN38-triggered EGF signals and IL-8 production in gastric cancer cells. Cancer Chemother Pharmacol 55:584–594PubMedCrossRefGoogle Scholar
  139. 139.
    Dragovich T, McCoy S, Fenoglio-Preiser CM et al (2006) Phase II trial of erlotinib in gastroesophageal junction and gastric adenocarcinomas: SWOG 0127. J Clin Oncol 24:4922–4927PubMedCrossRefGoogle Scholar
  140. 140.
    Ohtsu A, Shah MA, Van Cutsem E et al (2011) Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol 29:3968–3976PubMedCrossRefGoogle Scholar
  141. 141.
    Shen L, Li J, Xu J et al (2015) Bevacizumab plus capecitabine and cisplatin in Chinese patients with inoperable locally advanced or metastatic gastric or gastroesophageal junction cancer: randomized, double-blind, phase III study (AVATAR study). Gastric Cancer 18:168–176PubMedCrossRefGoogle Scholar
  142. 142.
    Fuchs CS, Tomasek J, Yong CJ et al (2014) Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet (London, England) 383:31–39CrossRefGoogle Scholar
  143. 143.
    Wilke H, Muro K, Van Cutsem E et al (2014) Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol 15:1224–1235PubMedCrossRefGoogle Scholar
  144. 144.
    Yoon HH, Bendell JC, Braiteh FS et al (2016) Ramucirumab combined with FOLFOX as front-line therapy for advanced esophageal, gastroesophageal junction, or gastric adenocarcinoma: a randomized, double-blind, multicenter phase II trial. Ann Oncol 27:2196–2203PubMedCrossRefGoogle Scholar
  145. 145.
    Geng R, Li J (2015) Apatinib for the treatment of gastric cancer. Expert Opin Pharmacother 16:117–122PubMedCrossRefGoogle Scholar
  146. 146.
    Li J, Qin S, Xu J et al (2013) Apatinib for chemotherapy-refractory advanced metastatic gastric cancer: results from a randomized, placebo-controlled, parallel-arm, phase II trial. J Clin Oncol 31:3219–3225PubMedCrossRefGoogle Scholar
  147. 147.
    Li J, Qin S, Xu J et al (2016) Randomized, double-blind, placebo-controlled phase III trial of Apatinib in patients with chemotherapy-refractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction. J Clin Oncol 34:1448–1454PubMedCrossRefGoogle Scholar
  148. 148.
    Zeng ZS, Weiser MR, Kuntz E et al (2008) c-Met gene amplification is associated with advanced stage colorectal cancer and liver metastases. Cancer Lett 265:258–269PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Christensen JG, Burrows J, Salgia R (2005) c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention. Cancer Lett 225:1–26PubMedCrossRefGoogle Scholar
  150. 150.
    Funakoshi Y, Mukohara T, Tomioka H et al (2013) Excessive MET signaling causes acquired resistance and addiction to MET inhibitors in the MKN45 gastric cancer cell line. Investig New Drugs 31:1158–1168CrossRefGoogle Scholar
  151. 151.
    Bachleitner-Hofmann T, Sun MY, Chen CT et al (2008) HER kinase activation confers resistance to MET tyrosine kinase inhibition in MET oncogene-addicted gastric cancer cells. Mol Cancer Ther 7:3499–3508PubMedCrossRefGoogle Scholar
  152. 152.
    Ahn SY, Kim J, Kim MA, Choi J, Kim WH (2017) Increased HGF expression induces resistance to c-MET tyrosine kinase inhibitors in gastric cancer. Anticancer Res 37:1127–1138PubMedCrossRefGoogle Scholar
  153. 153.
    Jin J, Xiong Y, Cen B (2017) Bcl-2 and Bcl-xL mediate resistance to receptor tyrosine kinase-targeted therapy in lung and gastric cancer. Anticancer Drugs 28:1141–1149PubMedCrossRefGoogle Scholar
  154. 154.
    Horii N, Morioka D, Yamaguchi K, Sato Y (2016) Remarkable response to trastuzumab observed in a case of gastric cancer with HER2-negative conversion. Gan To Kagaku Ryoho 43:1207–1209PubMedGoogle Scholar
  155. 155.
    Kelly CM, Janjigian YY (2016) The genomics and therapeutics of HER2-positive gastric cancer-from trastuzumab and beyond. J Gastrointest Oncol 7:750–762PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Zuo Q, Liu J, Zhang J, Wu M, Guo L, Liao W (2015) Development of trastuzumab-resistant human gastric carcinoma cell lines and mechanisms of drug resistance. Sci Rep 5:11634PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Han X, Diao L, Xu Y et al (2014) Association between the HER2 Ile655Val polymorphism and response to trastuzumab in women with operable primary breast cancer. Ann Oncol 25:1158–1164PubMedCrossRefGoogle Scholar
  158. 158.
    Torres-Jasso JH, Bustos-Carpinteyro AR, Marin ME et al (2013) Analysis of the polymorphisms EGFR-r521K and ERBB2-I655V in Mexican patients with gastric cancer and premalignant gastric lesions. Rev Investig Clin 65:150–155Google Scholar
  159. 159.
    Townsley CA, Major P, Siu LL et al (2006) Phase II study of erlotinib (OSI-774) in patients with metastatic colorectal cancer. Br J Cancer 94:1136–1143PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Xu W, Gong Y, Kuang M et al (2017) Survival benefit and safety of bevacizumab in combination with erlotinib as maintenance therapy in patients with metastatic colorectal cancer: a meta-analysis. Clin Drug Investig 37:155–165PubMedCrossRefGoogle Scholar
  161. 161.
    Philip PA, Mahoney MR, Allmer C et al (2005) Phase II study of erlotinib (OSI-774) in patients with advanced hepatocellular cancer. J Clin Oncol 23:6657–6663PubMedCrossRefGoogle Scholar
  162. 162.
    Zhang J, Zong Y, Xu GZ, Xing K (2016) Erlotinib for advanced hepatocellular carcinoma. A systematic review of phase II/III clinical trials. Saudi Med J 37:1184–1190PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    Fountzilas C, Chhatrala R, Khushalani N et al (2017) A phase II trial of erlotinib monotherapy in advanced pancreatic cancer as a first- or second-line agent. Cancer Chemother Pharmacol 80:497–505PubMedCrossRefGoogle Scholar
  164. 164.
    Feng R, Yang S (2016) Effects of combining erlotinib and RNA-interfered downregulation of focal adhesion kinase expression on gastric cancer. J Int Med Res 44:855–864PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Kuo T, Cho CD, Halsey J et al (2005) Phase II study of gefitinib, fluorouracil, leucovorin, and oxaliplatin therapy in previously treated patients with metastatic colorectal cancer. J Clin Oncol 23:5613–5619PubMedCrossRefGoogle Scholar
  166. 166.
    Zhang Y, Xiao Q, Zhang H et al (2014) Adenomatous polyposis coli determines sensitivity to the EGFR tyrosine kinase inhibitor gefitinib in colorectal cancer cells. Oncol Rep 31:1811–1817PubMedCrossRefGoogle Scholar
  167. 167.
    Schiffer E, Housset C, Cacheux W et al (2005) Gefitinib, an EGFR inhibitor, prevents hepatocellular carcinoma development in the rat liver with cirrhosis. Hepatology 41:307–314PubMedCrossRefGoogle Scholar
  168. 168.
    Hopfner M, Sutter AP, Huether A, Schuppan D, Zeitz M, Scherubl H (2004) Targeting the epidermal growth factor receptor by gefitinib for treatment of hepatocellular carcinoma. J Hepatol 41:1008–1016PubMedCrossRefGoogle Scholar
  169. 169.
    Shao J, Xu Z, Peng X et al (2016) Gefitinib synergizes with irinotecan to suppress hepatocellular carcinoma via antagonizing Rad51-mediated DNA-repair. PLoS One 11:e0146968PubMedPubMedCentralCrossRefGoogle Scholar
  170. 170.
    Li J, Kleeff J, Giese N, Buchler MW, Korc M, Friess H (2004) Gefitinib (‘Iressa’, ZD1839), a selective epidermal growth factor receptor tyrosine kinase inhibitor, inhibits pancreatic cancer cell growth, invasion, and colony formation. Int J Oncol 25:203–210PubMedGoogle Scholar
  171. 171.
    Fountzilas G, Bobos M, Kalogera-Fountzila A et al (2008) Gemcitabine combined with gefitinib in patients with inoperable or metastatic pancreatic cancer: a phase II study of the Hellenic Cooperative Oncology Group with biomarker evaluation. Cancer Investig 26:784–793CrossRefGoogle Scholar
  172. 172.
    Brell JM, Matin K, Evans T et al (2009) Phase II study of docetaxel and gefitinib as second-line therapy in gemcitabine pretreated patients with advanced pancreatic cancer. Oncology 76:270–274PubMedCrossRefGoogle Scholar
  173. 173.
    Xiao Z, Ding N, Xiao G, Wang S, Wu Y, Tang L (2012) Reversal of multidrug resistance by gefitinib via RAF1/ERK pathway in pancreatic cancer cell line. Anat Rec (Hoboken) 295:2122–2128CrossRefGoogle Scholar
  174. 174.
    Rojo F, Tabernero J, Albanell J et al (2006) Pharmacodynamic studies of gefitinib in tumor biopsy specimens from patients with advanced gastric carcinoma. J Clin Oncol 24:4309–4316PubMedCrossRefGoogle Scholar
  175. 175.
    Wang WP, Wang KN, Gao Q, Chen LQ (2012) Lack of EGFR mutations benefiting gefitinib treatment in adenocarcinoma of esophagogastric junction. World J Surg Oncol 10:14PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Fields ALA, Rinaldi DA, Henderson CA et al (2005) An open-label multicenter phase II study of oral lapatinib (GW572016) as single agent, second-line therapy in patients with metastatic colorectal cancer. J Clin Oncol 23:3583–3583CrossRefGoogle Scholar
  177. 177.
    Sartore-Bianchi A, Trusolino L, Martino C et al (2016) Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial. Lancet Oncol 17:738–746PubMedCrossRefPubMedCentralGoogle Scholar
  178. 178.
    Zhang WJ, Li Y, Wei MN et al (2017) Synergistic antitumor activity of regorafenib and lapatinib in preclinical models of human colorectal cancer. Cancer Lett 386:100–109PubMedCrossRefPubMedCentralGoogle Scholar
  179. 179.
    Bekaii-Saab T, Markowitz J, Prescott N et al (2009) A multi-institutional phase II study of the efficacy and tolerability of lapatinib in patients with advanced hepatocellular carcinomas. Clin Cancer Res 15:5895–5901PubMedPubMedCentralCrossRefGoogle Scholar
  180. 180.
    Ramanathan RK, Belani CP, Singh DA et al (2009) A phase II study of lapatinib in patients with advanced biliary tree and hepatocellular cancer. Cancer Chemother Pharmacol 64:777–783PubMedCrossRefPubMedCentralGoogle Scholar
  181. 181.
    Chen YJ, Chi CW, Su WC, Huang HL (2014) Lapatinib induces autophagic cell death and inhibits growth of human hepatocellular carcinoma. Oncotarget 5:4845–4854PubMedPubMedCentralGoogle Scholar
  182. 182.
    Yan YY, Guo Y, Zhang W et al (2014) Celastrol enhanced the anticancer effect of lapatinib in human hepatocellular carcinoma cells in vitro. J BUON 19:412–418PubMedPubMedCentralGoogle Scholar
  183. 183.
    Safran H, Miner T, Bahary N et al (2009) Lapatinib and gemcitabine for metastatic pancreatic cancer: a phase II study. J Clin Oncol 27:e15653–e15653Google Scholar
  184. 184.
    Safran H, Miner T, Bahary N et al (2011) Lapatinib and gemcitabine for metastatic pancreatic cancer. A phase II study. Am J Clin Oncol 34:50–52PubMedCrossRefGoogle Scholar
  185. 185.
    Murata A, Nakata B, Komoto M et al (2013) In vitro effects of lapatinib with gemcitabine for pancreatic cancer cells. Hepatogastroenterology 60:1484–1487PubMedPubMedCentralGoogle Scholar
  186. 186.
    Wu Z, Gabrielson A, Hwang JJ et al (2015) Phase II study of lapatinib and capecitabine in second-line treatment for metastatic pancreatic cancer. Cancer Chemother Pharmacol 76:1309–1314PubMedCrossRefPubMedCentralGoogle Scholar
  187. 187.
    Wainberg ZA, Anghel A, Desai AJ et al (2010) Lapatinib, a dual EGFR and HER2 kinase inhibitor, selectively inhibits HER2-amplified human gastric cancer cells and is synergistic with trastuzumab in vitro and in vivo. Clin Cancer Res 16:1509–1519PubMedCrossRefPubMedCentralGoogle Scholar
  188. 188.
    Iqbal S, Goldman B, Fenoglio-Preiser CM et al (2011) Southwest Oncology Group study S0413: a phase II trial of lapatinib (GW572016) as first-line therapy in patients with advanced or metastatic gastric cancer. Ann Oncol 22:2610–2615PubMedPubMedCentralCrossRefGoogle Scholar
  189. 189.
    Press MF, Ellis CE, Gagnon RC et al (2017) HER2 status in advanced or metastatic gastric, esophageal, or gastroesophageal adenocarcinoma for entry to the TRIO-013/LOGiC trial of lapatinib. Mol Cancer Ther 16:228–238PubMedCrossRefPubMedCentralGoogle Scholar
  190. 190.
    Sharma S, Abhyankar V, Burgess RE et al (2010) A phase I study of axitinib (AG-013736) in combination with bevacizumab plus chemotherapy or chemotherapy alone in patients with metastatic colorectal cancer and other solid tumors. Ann Oncol 21:297–304PubMedCrossRefPubMedCentralGoogle Scholar
  191. 191.
    Infante JR, Reid TR, Cohn AL et al (2013) Axitinib and/or bevacizumab with modified FOLFOX-6 as first-line therapy for metastatic colorectal cancer: a randomized phase 2 study. Cancer 119:2555–2563PubMedCrossRefPubMedCentralGoogle Scholar
  192. 192.
    Bendell JC, Tournigand C, Swieboda-Sadlej A et al (2013) Axitinib or bevacizumab plus FOLFIRI or modified FOLFOX-6 after failure of first-line therapy for metastatic colorectal cancer: a randomized phase II study. Clin Color Cancer 12:239–247CrossRefGoogle Scholar
  193. 193.
    Kang YK, Yau T, Park JW et al (2015) Randomized phase II study of axitinib versus placebo plus best supportive care in second-line treatment of advanced hepatocellular carcinoma. Ann Oncol 26:2457–2463PubMedPubMedCentralGoogle Scholar
  194. 194.
    Zhang B, Zhang X, Zhou T, Liu J (2015) Clinical observation of liver cancer patients treated with axitinib and cabozantinib after failed sorafenib treatment: a case report and literature review. Cancer Biol Ther 16:215–218PubMedPubMedCentralCrossRefGoogle Scholar
  195. 195.
    Spano JP, Moore MJ, Pithavala YK, Ricart AD, Kim S, Rixe O (2012) Phase I study of axitinib (AG-013736) in combination with gemcitabine in patients with advanced pancreatic cancer. Investig New Drugs 30:1531–1539CrossRefGoogle Scholar
  196. 196.
    Ioka T, Okusaka T, Ohkawa S et al (2015) Efficacy and safety of axitinib in combination with gemcitabine in advanced pancreatic cancer: subgroup analyses by region, including Japan, from the global randomized phase III trial. Jpn J Clin Oncol 45:439–448PubMedPubMedCentralCrossRefGoogle Scholar
  197. 197.
    Hoh CK, Burris HA 3rd, Bendell JC et al (2014) Intermittent dosing of axitinib combined with chemotherapy is supported by (18)FLT-PET in gastrointestinal tumours. Br J Cancer 110:875–881PubMedPubMedCentralCrossRefGoogle Scholar
  198. 198.
    He Q, Gao J, Ge S et al (2014) Axitinib alone or in combination with chemotherapeutic drugs exerts potent antitumor activity against human gastric cancer cells in vitro and in vivo. J Cancer Res Clin Oncol 140:1575–1583PubMedCrossRefPubMedCentralGoogle Scholar
  199. 199.
    Oh DY, Doi T, Shirao K et al (2015) Phase I study of axitinib in combination with cisplatin and capecitabine in patients with previously untreated advanced gastric cancer. Cancer Res Treat 47:687–696PubMedPubMedCentralCrossRefGoogle Scholar
  200. 200.
    Wangxia LV, Meiqin Y, Yunshan Y, Zhong S, Haijun Z (2017) The efficacy and safety of apatinib in patients with metastatic colorectal cancer refractory to standard therapies. J Clin Oncol 35:e15003–e15003CrossRefGoogle Scholar
  201. 201.
    Lu W, Ke H, Qianshan D, Zhen W, Guoan X, Honggang Y (2017) Apatinib has anti-tumor effects and induces autophagy in colon cancer cells. Iran J Basic Med Sci 20:990–995PubMedPubMedCentralGoogle Scholar
  202. 202.
    Qin S (2014) Apatinib in Chinese patients with advanced hepatocellular carcinoma: a phase II randomized, open-label trial. J Clin Oncol 32:4019–4019Google Scholar
  203. 203.
    Lu W, Jin XL, Yang C et al (2017) Comparison of efficacy between TACE combined with apatinib and TACE alone in the treatment of intermediate and advanced hepatocellular carcinoma: a single-center randomized controlled trial. Cancer Biol Ther 18:433–438PubMedPubMedCentralCrossRefGoogle Scholar
  204. 204.
    Liu C, Xing W, Si T, Yu H, Guo Z (2017) Efficacy and safety of apatinib combined with transarterial chemoembolization for hepatocellular carcinoma with portal venous tumor thrombus: a retrospective study. Oncotarget 8:100734–100745PubMedPubMedCentralGoogle Scholar
  205. 205.
    Li CM, Liu ZC, Bao YT, Sun XD, Wang LL (2017) Extraordinary response of metastatic pancreatic cancer to apatinib after failed chemotherapy: a case report and literature review. World J Gastroenterol 23:7478–7488PubMedPubMedCentralCrossRefGoogle Scholar
  206. 206.
    Liang L, Wang L, Zhu P et al (2017) Apatinib concurrent gemcitabine for controlling malignant ascites in advanced pancreatic cancer patient: a case report. Medicine 96:e8725PubMedPubMedCentralCrossRefGoogle Scholar
  207. 207.
    Han T, Luan Y, Xu Y et al (2017) Successful treatment of advanced pancreatic liposarcoma with apatinib: a case report and literature review. Cancer Biol Ther 18:635–639PubMedPubMedCentralCrossRefGoogle Scholar
  208. 208.
    Brower V (2016) Apatinib in treatment of refractory gastric cancer. Lancet Oncol 17:e137PubMedCrossRefPubMedCentralGoogle Scholar
  209. 209.
    Zhang W, Tan Y, Ma H (2017) Combined aspirin and apatinib treatment suppresses gastric cancer cell proliferation. Oncol Lett 14:5409–5417PubMedPubMedCentralGoogle Scholar
  210. 210.
    Zhang Y, Han C, Li J et al (2017) Efficacy and safety for Apatinib treatment in advanced gastric cancer: a real world study. Sci Rep 7:13208PubMedPubMedCentralCrossRefGoogle Scholar
  211. 211.
    Saltz LB, Meropol NJ, Loehrer PJ Sr, Needle MN, Kopit J, Mayer RJ (2004) Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 22:1201–1208PubMedCrossRefGoogle Scholar
  212. 212.
    Jonker DJ, O’Callaghan CJ, Karapetis CS et al (2007) Cetuximab for the treatment of colorectal cancer. N Engl J Med 357:2040–2048PubMedPubMedCentralCrossRefGoogle Scholar
  213. 213.
    Reynolds NA, Wagstaff AJ (2004) Cetuximab: in the treatment of metastatic colorectal cancer. Drugs 64:109–118 discussion 119–121PubMedCrossRefGoogle Scholar
  214. 214.
    Guren TK, Thomsen M, Kure EH et al (2017) Cetuximab in treatment of metastatic colorectal cancer: final survival analyses and extended RAS data from the NORDIC-VII study. Br J Cancer 116:1271–1278PubMedPubMedCentralCrossRefGoogle Scholar
  215. 215.
    Zhu AX, Stuart K, Blaszkowsky LS et al (2007) Phase 2 study of cetuximab in patients with advanced hepatocellular carcinoma. Cancer 110:581–589PubMedCrossRefGoogle Scholar
  216. 216.
    Asnacios A, Fartoux L, Romano O et al (2008) Gemcitabine plus oxaliplatin (GEMOX) combined with cetuximab in patients with progressive advanced stage hepatocellular carcinoma: results of a multicenter phase 2 study. Cancer 112:2733–2739PubMedCrossRefGoogle Scholar
  217. 217.
    Sanoff HK, Bernard S, Goldberg RM et al (2011) Phase II study of capecitabine, oxaliplatin, and cetuximab for advanced hepatocellular carcinoma. Gastrointest Cancer Res 4:78–83PubMedPubMedCentralGoogle Scholar
  218. 218.
    Geng J, Li X, Lang X et al (2014) Combination of cetuximab and rapamycin enhances the therapeutic efficacy in hepatocellular carcinoma. Technol Cancer Res Treat 13:377–385PubMedCrossRefGoogle Scholar
  219. 219.
    Cascinu S, Berardi R, Labianca R et al (2008) Cetuximab plus gemcitabine and cisplatin compared with gemcitabine and cisplatin alone in patients with advanced pancreatic cancer: a randomised, multicentre, phase II trial. Lancet Oncol 9:39–44CrossRefGoogle Scholar
  220. 220.
    Luedke E, Jaime-Ramirez AC, Bhave N, Carson WE 3rd (2012) Monoclonal antibody therapy of pancreatic cancer with cetuximab: potential for immune modulation. J Immunother 35:367–373PubMedPubMedCentralCrossRefGoogle Scholar
  221. 221.
    Burtness B, Powell M, Catalano P et al (2016) Randomized phase II trial of irinotecan/docetaxel or irinotecan/docetaxel plus cetuximab for metastatic pancreatic cancer: an Eastern Cooperative Oncology Group Study. Am J Clin Oncol 39:340–345PubMedPubMedCentralCrossRefGoogle Scholar
  222. 222.
    Hara M, Nakanishi H, Tsujimura K et al (2008) Interleukin-2 potentiation of cetuximab antitumor activity for epidermal growth factor receptor-overexpressing gastric cancer xenografts through antibody-dependent cellular cytotoxicity. Cancer Sci 99:1471–1478PubMedCrossRefGoogle Scholar
  223. 223.
    Shi M, Ji J, Wu J et al (2012) Cetuximab combined with FOLFOX4 as the first-line treatment for advanced gastric cancer: report of 25 cases from a single institution. Hepatogastroenterology 59:1054–1058PubMedGoogle Scholar
  224. 224.
    Ji L, Gu D, Tan X, Sun H, Chen J (2017) A meta-analysis of clinical trials over regimens with or without cetuximab for advanced gastric cancer patients. J BUON 22:900–904PubMedGoogle Scholar
  225. 225.
    Weber J, McCormack PL (2008) Panitumumab: in metastatic colorectal cancer with wild-type KRAS. BioDrugs 22:403–411PubMedCrossRefGoogle Scholar
  226. 226.
    Giusti RM, Cohen MH, Keegan P, Pazdur R (2009) FDA review of a panitumumab (Vectibix) clinical trial for first-line treatment of metastatic colorectal cancer. Oncologist 14:284–290PubMedCrossRefGoogle Scholar
  227. 227.
    Battaglin F, Dadduzio V, Bergamo F et al (2017) Anti-EGFR monoclonal antibody panitumumab for the treatment of patients with metastatic colorectal cancer: an overview of current practice and future perspectives. Expert Opin Biol Ther 17:1297–1308PubMedCrossRefPubMedCentralGoogle Scholar
  228. 228.
    Terada I, Amaya K, Watanabe T et al (2015) A case of simultaneous laparoscopic resection of sigmoid colon cancer and liver metastases after chemotherapy with modified FOLFOX6 plus panitumumab. Gan To Kagaku Ryoho 42:2166–2168PubMedPubMedCentralGoogle Scholar
  229. 229.
    Yagi Y, Yamazaki T, Iwaya A, Manabe S (2015) Preoperative chemotherapy with modified FOLFOX + panitumumab for the treatment of descending colon cancer with multiple liver metastases – a case study. Gan To Kagaku Ryoho 42:109–112PubMedGoogle Scholar
  230. 230.
    Lindberg JM, Newhook TE, Adair SJ et al (2014) Co-treatment with panitumumab and trastuzumab augments response to the MEK inhibitor trametinib in a patient-derived xenograft model of pancreatic cancer. Neoplasia 16:562–571PubMedPubMedCentralCrossRefGoogle Scholar
  231. 231.
    Berry W, Algar E, Kumar B et al (2017) Endoscopic ultrasound-guided fine-needle aspirate-derived preclinical pancreatic cancer models reveal panitumumab sensitivity in KRAS wild-type tumors. Int J Cancer 140:2331–2343PubMedCrossRefGoogle Scholar
  232. 232.
    Tebbutt NC, Price TJ, Ferraro DA et al (2016) Panitumumab added to docetaxel, cisplatin and fluoropyrimidine in oesophagogastric cancer: ATTAX3 phase II trial. Br J Cancer 114:505–509PubMedPubMedCentralCrossRefGoogle Scholar
  233. 233.
    Jin T, Zhu Y, Luo JL et al (2015) Prospective phase II trial of nimotuzumab in combination with radiotherapy and concurrent capecitabine in locally advanced rectal cancer. Int J Color Dis 30:337–345CrossRefGoogle Scholar
  234. 234.
    Song P, Yang J, Li X et al (2017) Hepatocellular carcinoma treated with anti-epidermal growth factor receptor antibody nimotuzumab: a case report. Medicine (Baltimore) 96:e8122CrossRefGoogle Scholar
  235. 235.
    Strumberg D, Schultheis B, Scheulen ME et al (2012) Phase II study of nimotuzumab, a humanized monoclonal anti-epidermal growth factor receptor (EGFR) antibody, in patients with locally advanced or metastatic pancreatic cancer. Investig New Drugs 30:1138–1143CrossRefGoogle Scholar
  236. 236.
    Su D, Jiao SC, Wang LJ et al (2014) Efficacy of nimotuzumab plus gemcitabine usage as first-line treatment in patients with advanced pancreatic cancer. Tumour Biol 35:2313–2318PubMedCrossRefGoogle Scholar
  237. 237.
    Schultheis B, Reuter D, Ebert MP et al (2017) Gemcitabine combined with the monoclonal antibody nimotuzumab is an active first-line regimen in KRAS wildtype patients with locally advanced or metastatic pancreatic cancer: a multicenter, randomized phase IIb study. Ann Oncol 28:2429–2435PubMedCrossRefGoogle Scholar
  238. 238.
    Zhou C, Zhu L, Ji J et al (2017) EGFR high expression, but not KRAS status, predicts sensitivity of pancreatic cancer cells to nimotuzumab treatment in vivo. Curr Cancer Drug Targets 17:89–97PubMedCrossRefPubMedCentralGoogle Scholar
  239. 239.
    Du F, Zheng Z, Shi S et al (2015) S-1 and cisplatin with or without nimotuzumab for patients with untreated unresectable or metastatic gastric cancer: a randomized, open-label phase 2 trial. Medicine (Baltimore) 94:e958CrossRefGoogle Scholar
  240. 240.
    Satoh T, Lee KH, Rha SY et al (2015) Randomized phase II trial of nimotuzumab plus irinotecan versus irinotecan alone as second-line therapy for patients with advanced gastric cancer. Gastric Cancer 18:824–832PubMedCrossRefGoogle Scholar
  241. 241.
    Han X, Lu N, Pan Y, Nimotuzumab XJ (2017) Combined with chemotherapy is a promising treatment for locally advanced and metastatic esophageal cancer. Med Sci Monit Int Med J Exp Clin Res 23:412–418Google Scholar
  242. 242.
    Ramanathan RK, Hwang JJ, Zamboni WC et al (2004) Low overexpression of HER-2/neu in advanced colorectal cancer limits the usefulness of trastuzumab (Herceptin) and irinotecan as therapy. A phase II trial. Cancer Investig 22:858–865CrossRefGoogle Scholar
  243. 243.
    Sartore-Bianchi A, Trusolino L, Martino C et al Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, <em>KRAS</em> codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial. Lancet Oncol 17:738–746Google Scholar
  244. 244.
    Xian ZH, Zhang SH, Cong WM, Wu WQ, Wu MC (2005) Overexpression/amplification of HER-2/neu is uncommon in hepatocellular carcinoma. J Clin Pathol 58:500–503PubMedPubMedCentralCrossRefGoogle Scholar
  245. 245.
    Hsu C, Huang CL, Hsu HC, Lee PH, Wang SJ, Cheng AL (2002) HER-2/neu overexpression is rare in hepatocellular carcinoma and not predictive of anti-HER-2/neu regulation of cell growth and chemosensitivity. Cancer 94:415–420PubMedCrossRefGoogle Scholar
  246. 246.
    Tatebe H, Shimizu M, Shirakami Y, Tsurumi H, Moriwaki H (2008) Synergistic growth inhibition by 9-cis-retinoic acid plus trastuzumab in human hepatocellular carcinoma cells. Clin Cancer Res 14:2806–2812PubMedCrossRefGoogle Scholar
  247. 247.
    Kimura K, Sawada T, Komatsu M et al (2006) Antitumor effect of trastuzumab for pancreatic cancer with high HER-2 expression and enhancement of effect by combined therapy with gemcitabine. Clin Cancer Res 12:4925–4932PubMedCrossRefGoogle Scholar
  248. 248.
    Saeki H, Yanoma S, Takemiya S et al (2007) Antitumor activity of a combination of trastuzumab (Herceptin) and oral fluoropyrimidine S-1 on human epidermal growth factor receptor 2-overexpressing pancreatic cancer. Oncol Rep 18:433–439PubMedGoogle Scholar
  249. 249.
    Harder J, Ihorst G, Heinemann V et al (2012) Multicentre phase II trial of trastuzumab and capecitabine in patients with HER2 overexpressing metastatic pancreatic cancer. Br J Cancer 106:1033–1038PubMedPubMedCentralCrossRefGoogle Scholar
  250. 250.
    Assenat E, Azria D, Mollevi C et al (2015) Dual targeting of HER1/EGFR and HER2 with cetuximab and trastuzumab in patients with metastatic pancreatic cancer after gemcitabine failure: results of the “THERAPY” phase 1-2 trial. Oncotarget 6:12796–12808PubMedPubMedCentralCrossRefGoogle Scholar
  251. 251.
    Li Q, Li H, Jiang H, et al (2017) Predictive factors of trastuzumab-based chemotherapy in HER2 positive advanced gastric cancer: a single-center prospective observational study. Clin Transl Oncol 20(6):695-702PubMedCrossRefGoogle Scholar
  252. 252.
    Pohl M, Stricker I, Schoeneck A et al (2009) Antitumor activity of the HER2 dimerization inhibitor pertuzumab on human colon cancer cells in vitro and in vivo. J Cancer Res Clin Oncol 135:1377–1386PubMedCrossRefGoogle Scholar
  253. 253.
    Rubinson DA, Hochster HS, Ryan DP et al (2014) Multi-drug inhibition of the HER pathway in metastatic colorectal cancer: results of a phase I study of pertuzumab plus cetuximab in cetuximab-refractory patients. Investig New Drugs 32:113–122CrossRefGoogle Scholar
  254. 254.
    Javle MM, Hainsworth JD, Swanton C et al (2017) Pertuzumab + trastuzumab for HER2-positive metastatic biliary cancer: preliminary data from MyPathway. J Clin Oncol 35:402–402CrossRefGoogle Scholar
  255. 255.
    Thomas G, Chardes T, Gaborit N et al (2014) HER3 as biomarker and therapeutic target in pancreatic cancer: new insights in pertuzumab therapy in preclinical models. Oncotarget 5:7138–7148PubMedPubMedCentralCrossRefGoogle Scholar
  256. 256.
    Yamashita-Kashima Y, Iijima S, Yorozu K et al (2011) Pertuzumab in combination with trastuzumab shows significantly enhanced antitumor activity in HER2-positive human gastric cancer xenograft models. Clin Cancer Res 17:5060–5070PubMedCrossRefGoogle Scholar
  257. 257.
    Yamashita-Kashima Y, Shu S, Harada N, Fujimoto-Ouchi K (2013) Enhanced antitumor activity of trastuzumab emtansine (T-DM1) in combination with pertuzumab in a HER2-positive gastric cancer model. Oncol Rep 30:1087–1093PubMedCrossRefGoogle Scholar
  258. 258.
    Bendell JC, Joseph M, Barnes K et al (2017) A phase-2 trial of single agent axitinib as maintenance therapy following first-line treatment with modified FOLFOX/bevacizumab in patients with metastatic colorectal cancer. Cancer Investig 35:386–392CrossRefGoogle Scholar
  259. 259.
    Boige V, Malka D, Bourredjem A et al (2012) Efficacy, safety, and biomarkers of single-agent bevacizumab therapy in patients with advanced hepatocellular carcinoma. Oncologist 17:1063–1072PubMedPubMedCentralCrossRefGoogle Scholar
  260. 260.
    Siegel AB, Cohen EI, Ocean A et al (2008) Phase II trial evaluating the clinical and biologic effects of bevacizumab in unresectable hepatocellular carcinoma. J Clin Oncol 26:2992–2998PubMedPubMedCentralCrossRefGoogle Scholar
  261. 261.
    Philip PA, Mahoney MR, Holen KD et al (2012) Phase 2 study of bevacizumab plus erlotinib in patients with advanced hepatocellular cancer. Cancer 118:2424–2430PubMedCrossRefGoogle Scholar
  262. 262.
    Kaseb AO, Morris JS, Iwasaki M et al (2016) Phase II trial of bevacizumab and erlotinib as a second-line therapy for advanced hepatocellular carcinoma. Onco Targets Ther 9:773–780PubMedPubMedCentralCrossRefGoogle Scholar
  263. 263.
    Pasquale DE, de Ville de Goyet J, Monti L, Grimaldi C, Crocoli A, Castellano A (2017) Bevacizumab combined with chemotherapy in children affected by hepatocellular carcinoma: a single-center experience. Anticancer Res 37:1489–1493CrossRefGoogle Scholar
  264. 264.
    Shao YY, Lin ZZ, Liang PC, Tien YW, Cheng AL (2009) Gastric perforation presenting as empyema in a patient with pancreatic cancer on bevacizumab treatment. Anticancer Res 29:1665–1667PubMedGoogle Scholar
  265. 265.
    Ko AH, Venook AP, Bergsland EK et al (2010) A phase II study of bevacizumab plus erlotinib for gemcitabine-refractory metastatic pancreatic cancer. Cancer Chemother Pharmacol 66:1051–1057PubMedCrossRefGoogle Scholar
  266. 266.
    Pant S, Martin LK, Geyer S et al (2014) Baseline serum albumin is a predictive biomarker for patients with advanced pancreatic cancer treated with bevacizumab: a pooled analysis of 7 prospective trials of gemcitabine-based therapy with or without bevacizumab. Cancer 120:1780–1786PubMedPubMedCentralCrossRefGoogle Scholar
  267. 267.
    Tai CJ, Wang H, Wang CK et al (2017) Bevacizumab and cetuximab with conventional chemotherapy reduced pancreatic tumor weight in mouse pancreatic cancer xenografts. Clin Exp Med 17:141–150PubMedCrossRefGoogle Scholar
  268. 268.
    Ninomiya S, Inomata M, Tajima M et al (2009) Effect of bevacizumab, a humanized monoclonal antibody to vascular endothelial growth factor, on peritoneal metastasis of MNK-45P human gastric cancer in mice. J Surg Res 154:196–202PubMedCrossRefGoogle Scholar
  269. 269.
    Imaizumi T, Aoyagi K, Miyagi M, Shirouzu K (2010) Suppressive effect of bevacizumab on peritoneal dissemination from gastric cancer in a peritoneal metastasis model. Surg Today 40:851–857PubMedCrossRefGoogle Scholar
  270. 270.
    Aoyagi K, Kouhuji K, Miyagi M et al (2013) Molecular targeting therapy using bevacizumab for peritoneal metastasis from gastric cancer. World J Crit Care Med 2:48–55PubMedPubMedCentralCrossRefGoogle Scholar
  271. 271.
    Lv Y, Song L, Chang L et al (2016) Bevacizumab followed by chemotherapy is potential therapy for gastric cancer. J BUON 21:1466–1470PubMedGoogle Scholar
  272. 272.
    Garcia-Carbonero R, Rivera F, Maurel J et al (2014) An open-label phase II study evaluating the safety and efficacy of ramucirumab combined with mFOLFOX-6 as first-line therapy for metastatic colorectal cancer. Oncologist 19:350–351PubMedPubMedCentralCrossRefGoogle Scholar
  273. 273.
    Tabernero J, Yoshino T, Cohn AL et al (2015) Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol 16:499–508PubMedCrossRefGoogle Scholar
  274. 274.
    Gambardella V, Tarazona N, Cejalvo JM, Rosello S, Cervantes A (2016) Clinical pharmacokinetics and pharmacodynamics of ramucirumab in the treatment of colorectal cancer. Expert Opin Drug Metab Toxicol 12:449–456PubMedCrossRefGoogle Scholar
  275. 275.
    Yoshino T, Obermannova R, Bodoky G et al (2017) Baseline carcinoembryonic antigen as a predictive factor of ramucirumab efficacy in RAISE, a second-line metastatic colorectal carcinoma phase III trial. Eur J Cancer 78:61–69PubMedCrossRefGoogle Scholar
  276. 276.
    Zhu AX, Finn RS, Mulcahy M et al (2013) A phase II and biomarker study of ramucirumab, a human monoclonal antibody targeting the VEGF receptor-2, as first-line monotherapy in patients with advanced hepatocellular cancer. Clin Cancer Res 19:6614–6623PubMedPubMedCentralCrossRefGoogle Scholar
  277. 277.
    Zhu AX, Park JO, Ryoo BY et al (2015) Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial. Lancet Oncol 16:859–870PubMedCrossRefGoogle Scholar
  278. 278.
    Park JO, Ryoo BY, Yen CJ et al (2016) Second-line ramucirumab therapy for advanced hepatocellular carcinoma (REACH): an East Asian and non-East Asian subgroup analysis. Oncotarget 7:75482–75491PubMedPubMedCentralGoogle Scholar
  279. 279.
    Kudo M, Hatano E, Ohkawa S et al (2017) Ramucirumab as second-line treatment in patients with advanced hepatocellular carcinoma: Japanese subgroup analysis of the REACH trial. J Gastroenterol 52:494–503PubMedCrossRefGoogle Scholar
  280. 280.
    Mosquera C, Maglic D, Zervos EE (2016) Molecular targeted therapy for pancreatic adenocarcinoma: a review of completed and ongoing late phase clinical trials. Cancer Genet 209:567–581PubMedCrossRefGoogle Scholar
  281. 281.
    Javle M, Smyth EC, Chau I (2014) Ramucirumab: successfully targeting angiogenesis in gastric cancer. Clin Cancer Res 20:5875–5881PubMedPubMedCentralCrossRefGoogle Scholar
  282. 282.
    Muro K, Oh SC, Shimada Y et al (2016) Subgroup analysis of East Asians in RAINBOW: a phase 3 trial of ramucirumab plus paclitaxel for advanced gastric cancer. J Gastroenterol Hepatol 31:581–589PubMedCrossRefGoogle Scholar
  283. 283.
    Kimura Y, Makari Y, Mikami J et al (2016) Clinical experience of ramucirumab for treating advanced gastric cancer. Gan To Kagaku Ryoho 43:1193–1196PubMedGoogle Scholar
  284. 284.
    Muro K, Cho JY, Bodoky G, et al (2018) Age does not influence efficacy of ramucirumab in advanced gastric cancer: subgroup analyses of REGARD and RAINBOW. J Gastroenterol Hepatol 33(4):814–824PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2018

Authors and Affiliations

  • L. V. K. S. Bhaskar
    • 1
  • L. Saikrishna
    • 2
  1. 1.Sickle Cell Institute ChhattisgarhRaipurIndia
  2. 2.Sri Venkateswara UniversityTirupatiIndia

Personalised recommendations