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Targeted Therapies Against Growth Factor Signaling in Breast Cancer

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Translational Research in Breast Cancer

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1026))

Abstract

Breast cancer is the most prevalent female malignancy throughout the world. Conventional treatment strategies for breast cancer consist of chemotherapy, radiation, surgery, chemoradiation, hormone therapy, and targeted therapies. Among them, targeted therapies show advantages to reduce cost and toxicity for being possible for individualized treatments based on the intrinsic subtypes of breast cancer. With deeper understanding of key signaling pathways concerning tumor growth and survival, growth factor-controlled signaling pathways are frequently dysregulated in the development and progression of breast cancer. Thus, targeted therapies against growth factor-mediated signaling pathways have been shown to have promising efficacy in both preclinical animal models and human clinical trials. In this chapter, we will briefly introduce inhibitors and monoclonal antibodies that target the main growth factor-modulated scenarios including epidermal growth factor receptor (EGFR), transforming growth factor beta (TGF-β), insulin-like growth factor 1 receptor (IGF1R), and fibroblast growth factor receptor (FGFR) signaling pathways in breast cancer therapy.

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References

  1. Lemmon MA, Schlessinger J (2010) Cell signaling by receptor tyrosine kinases. Cell 141(7):1117–1134. doi:10.1016/j.cell.2010.06.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Cohen S (1983) The epidermal growth factor (EGF). Cancer 51(10):1787–1791

    Article  CAS  PubMed  Google Scholar 

  3. Roskoski R Jr (2014) The ErbB/HER family of protein-tyrosine kinases and cancer. Pharmacol Res 79:34–74. doi:10.1016/j.phrs.2013.11.002

    Article  CAS  PubMed  Google Scholar 

  4. Cohen S, Ushiro H, Stoscheck C, Chinkers M (1982) A native 170,000 epidermal growth factor receptor-kinase complex from shed plasma membrane vesicles. J Biol Chem 257(3):1523–1531

    CAS  PubMed  Google Scholar 

  5. Cohen S, Fava RA, Sawyer ST (1982) Purification and characterization of epidermal growth factor receptor/protein kinase from normal mouse liver. Proc Natl Acad Sci U S A 79(20):6237–6241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Park OK, Schaefer TS, Nathans D (1996) In vitro activation of Stat3 by epidermal growth factor receptor kinase. Proc Natl Acad Sci U S A 93(24):13704–13708

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Anderson D, Koch CA, Grey L, Ellis C, Moran MF, Pawson T (1990) Binding of SH2 domains of phospholipase C gamma 1, GAP, and Src to activated growth factor receptors. Science 250(4983):979–982

    Article  CAS  PubMed  Google Scholar 

  8. Navolanic PM, Steelman LS, McCubrey JA (2003) EGFR family signaling and its association with breast cancer development and resistance to chemotherapy (review). Int J Oncol 22(2):237–252

    CAS  PubMed  Google Scholar 

  9. Yarden Y, Sliwkowski MX (2001) Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2(2):127–137. doi:10.1038/35052073

    Article  CAS  PubMed  Google Scholar 

  10. Vojtek AB, Hollenberg SM, Cooper JA (1993) Mammalian Ras interacts directly with the serine/threonine kinase Raf. Cell 74(1):205–214

    Article  CAS  PubMed  Google Scholar 

  11. Wu CJ, Qian X, O’Rourke DM (1999) Sustained mitogen-activated protein kinase activation is induced by transforming erbB receptor complexes. DNA Cell Biol 18(10):731–741. doi:10.1089/104454999314872

    Article  CAS  PubMed  Google Scholar 

  12. Hashimoto A, Kurosaki M, Gotoh N, Shibuya M, Kurosaki T (1999) Shc regulates epidermal growth factor-induced activation of the JNK signaling pathway. J Biol Chem 274(29):20139–20143

    Article  CAS  PubMed  Google Scholar 

  13. Voice JK, Klemke RL, Le A, Jackson JH (1999) Four human ras homologs differ in their abilities to activate Raf-1, induce transformation, and stimulate cell motility. J Biol Chem 274(24):17164–17170

    Article  CAS  PubMed  Google Scholar 

  14. Chan TO, Rodeck U, Chan AM, Kimmelman AC, Rittenhouse SE, Panayotou G, Tsichlis PN (2002) Small GTPases and tyrosine kinases coregulate a molecular switch in the phosphoinositide 3-kinase regulatory subunit. Cancer Cell 1(2):181–191

    Article  PubMed  Google Scholar 

  15. Pacold ME, Suire S, Perisic O, Lara-Gonzalez S, Davis CT, Walker EH, Hawkins PT, Stephens L, Eccleston JF, Williams RL (2000) Crystal structure and functional analysis of Ras binding to its effector phosphoinositide 3-kinase gamma. Cell 103(6):931–943

    Article  CAS  PubMed  Google Scholar 

  16. Walker EH, Perisic O, Ried C, Stephens L, Williams RL (1999) Structural insights into phosphoinositide 3-kinase catalysis and signalling. Nature 402(6759):313–320. doi:10.1038/46319

    Article  CAS  PubMed  Google Scholar 

  17. Darnell JE Jr, Kerr IM, Stark GR (1994) Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264(5164):1415–1421

    Article  CAS  PubMed  Google Scholar 

  18. Fu XY (1999) From PTK-STAT signaling to caspase expression and apoptosis induction. Cell Death Differ 6(12):1201–1208. doi:10.1038/sj.cdd.4400613

    Article  CAS  PubMed  Google Scholar 

  19. Barre B, Avril S, Coqueret O (2003) Opposite regulation of myc and p21waf1 transcription by STAT3 proteins. J Biol Chem 278(5):2990–2996. doi:10.1074/jbc.M210422200

    Article  CAS  PubMed  Google Scholar 

  20. Lo HW, Hsu SC, Ali-Seyed M, Gunduz M, Xia W, Wei Y, Bartholomeusz G, Shih JY, Hung MC (2005) Nuclear interaction of EGFR and STAT3 in the activation of the iNOS/NO pathway. Cancer Cell 7(6):575–589. doi:10.1016/j.ccr.2005.05.007

    Article  CAS  PubMed  Google Scholar 

  21. Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C, Darnell JE Jr (1999) Stat3 as an oncogene. Cell 98(3):295–303

    Article  CAS  PubMed  Google Scholar 

  22. Wei D, Le X, Zheng L, Wang L, Frey JA, Gao AC, Peng Z, Huang S, Xiong HQ, Abbruzzese JL, Xie K (2003) Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis. Oncogene 22(3):319–329. doi:10.1038/sj.onc.1206122

    Article  CAS  PubMed  Google Scholar 

  23. Niu G, Wright KL, Huang M, Song L, Haura E, Turkson J, Zhang S, Wang T, Sinibaldi D, Coppola D, Heller R, Ellis LM, Karras J, Bromberg J, Pardoll D, Jove R, Yu H (2002) Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 21(13):2000–2008. doi:10.1038/sj.onc.1205260

    Article  CAS  PubMed  Google Scholar 

  24. Yarden Y, Pines G (2012) The ERBB network: at last, cancer therapy meets systems biology. Nat Rev Cancer 12(8):553–563. doi:10.1038/nrc3309

    Article  CAS  PubMed  Google Scholar 

  25. Lianos GD, Vlachos K, Zoras O, Katsios C, Cho WC, Roukos DH (2014) Potential of antibody-drug conjugates and novel therapeutics in breast cancer management. Onco Targets Ther 7:491–500. doi:10.2147/OTT.S34235

    PubMed  PubMed Central  Google Scholar 

  26. Arteaga CL, Moulder SL, Yakes FM (2002) HER (erbB) tyrosine kinase inhibitors in the treatment of breast cancer. Semin Oncol 29(3 Suppl 11):4–10

    Article  CAS  PubMed  Google Scholar 

  27. Ciardiello F, Tortora G (2001) A novel approach in the treatment of cancer: targeting the epidermal growth factor receptor. Clin Cancer Res 7(10):2958–2970

    CAS  PubMed  Google Scholar 

  28. Mendelsohn J, Baselga J (2003) Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol 21(14):2787–2799. doi:10.1200/JCO.2003.01.504

    Article  CAS  PubMed  Google Scholar 

  29. Normanno N, De Luca A, Bianco C, Strizzi L, Mancino M, Maiello MR, Carotenuto A, De Feo G, Caponigro F, Salomon DS (2006) Epidermal growth factor receptor (EGFR) signaling in cancer. Gene 366(1):2–16. doi:10.1016/j.gene.2005.10.018

    Article  CAS  PubMed  Google Scholar 

  30. Lluch A, Eroles P, Perez-Fidalgo JA (2014) Emerging EGFR antagonists for breast cancer. Expert Opin Emerg Drugs 19(2):165–181. doi:10.1517/14728214.2014.903919

    Article  CAS  PubMed  Google Scholar 

  31. Howe LR, Brown PH (2011) Targeting the HER/EGFR/ErbB family to prevent breast cancer. Cancer Prev Res (Phila) 4(8):1149–1157. doi:10.1158/1940-6207.CAPR-11-0334

    Article  CAS  Google Scholar 

  32. Cho HS, Mason K, Ramyar KX, Stanley AM, Gabelli SB, Denney DW Jr, Leahy DJ (2003) Structure of the extracellular region of HER2 alone and in complex with the Herceptin fab. Nature 421(6924):756–760. doi:10.1038/nature01392

    Article  CAS  PubMed  Google Scholar 

  33. Baselga J, Albanell J, Molina MA, Arribas J (2001) Mechanism of action of trastuzumab and scientific update. Semin Oncol 28(5 Suppl 16):4–11

    Article  CAS  PubMed  Google Scholar 

  34. Varchetta S, Gibelli N, Oliviero B, Nardini E, Gennari R, Gatti G, Silva LS, Villani L, Tagliabue E, Menard S, Costa A, Fagnoni FF (2007) Elements related to heterogeneity of antibody-dependent cell cytotoxicity in patients under trastuzumab therapy for primary operable breast cancer overexpressing Her2. Cancer Res 67(24):11991–11999. doi:10.1158/0008-5472.CAN-07-2068

    Article  CAS  PubMed  Google Scholar 

  35. Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, Slamon DJ, Murphy M, Novotny WF, Burchmore M, Shak S, Stewart SJ, Press M (2002) Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 20(3):719–726. doi:10.1200/JCO.2002.20.3.719

    Article  CAS  PubMed  Google Scholar 

  36. Smith I, Procter M, Gelber RD, Guillaume S, Feyereislova A, Dowsett M, Goldhirsch A, Untch M, Mariani G, Baselga J, Kaufmann M, Cameron D, Bell R, Bergh J, Coleman R, Wardley A, Harbeck N, Lopez RI, Mallmann P, Gelmon K, Wilcken N, Wist E, Sanchez Rovira P, Piccart-Gebhart MJ (2007) 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 369(9555):29–36. doi:10.1016/S0140-6736(07)60028-2

    Article  CAS  PubMed  Google Scholar 

  37. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344(11):783–792. doi:10.1056/NEJM200103153441101

    Article  CAS  PubMed  Google Scholar 

  38. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, Gianni L, Baselga J, Bell R, Jackisch C, Cameron D, Dowsett M, Barrios CH, Steger G, Huang CS, Andersson M, Inbar M, Lichinitser M, Lang I, Nitz U, Iwata H, Thomssen C, Lohrisch C, Suter TM, Ruschoff J, Suto T, Greatorex V, Ward C, Straehle C, McFadden E, Dolci MS, Gelber RD (2005) Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353(16):1659–1672. doi:10.1056/NEJMoa052306

    Article  CAS  PubMed  Google Scholar 

  39. Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N (2005) Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353(16):1673–1684. doi:10.1056/NEJMoa052122

    Article  CAS  PubMed  Google Scholar 

  40. Hudis CA (2007) Trastuzumab--mechanism of action and use in clinical practice. N Engl J Med 357(1):39–51. doi:10.1056/NEJMra043186

    Article  CAS  PubMed  Google Scholar 

  41. Roukos DH (2011) Trastuzumab and beyond: sequencing cancer genomes and predicting molecular networks. Pharmacogenomics J 11(2):81–92. doi:10.1038/tpj.2010.81

    Article  CAS  PubMed  Google Scholar 

  42. Shepard HM, Brdlik CM, Schreiber H (2008) Signal integration: a framework for understanding the efficacy of therapeutics targeting the human EGFR family. J Clin Invest 118(11):3574–3581. doi:10.1172/JCI36049

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Rexer BN, Arteaga CL (2012) Intrinsic and acquired resistance to HER2-targeted therapies in HER2 gene-amplified breast cancer: mechanisms and clinical implications. Crit Rev Oncog 17(1):1–16

    Article  PubMed  PubMed Central  Google Scholar 

  44. Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, Jagiello-Gruszfeld A, Crown J, Chan A, Kaufman B, Skarlos D, Campone M, Davidson N, Berger M, Oliva C, Rubin SD, Stein S, Cameron D (2006) Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355(26):2733–2743. doi:10.1056/NEJMoa064320

    Article  CAS  PubMed  Google Scholar 

  45. Franklin MC, Carey KD, Vajdos FF, Leahy DJ, de Vos AM, Sliwkowski MX (2004) Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell 5(4):317–328

    Article  CAS  PubMed  Google Scholar 

  46. Baselga J, Cortes J, Kim SB, Im SA, Hegg R, Im YH, Roman L, Pedrini JL, Pienkowski T, Knott A, Clark E, Benyunes MC, Ross G, Swain SM (2012) Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 366(2):109–119. doi:10.1056/NEJMoa1113216

    Article  CAS  PubMed  Google Scholar 

  47. Blumenthal GM, Scher NS, Cortazar P, Chattopadhyay S, Tang S, Song P, Liu Q, Ringgold K, Pilaro AM, Tilley A, King KE, Graham L, Rellahan BL, Weinberg WC, Chi B, Thomas C, Hughes P, Ibrahim A, Justice R, Pazdur R (2013) First FDA approval of dual anti-HER2 regimen: pertuzumab in combination with trastuzumab and docetaxel for HER2-positive metastatic breast cancer. Clin Cancer Res 19(18):4911–4916. doi:10.1158/1078-0432.CCR-13-1212

    Article  CAS  PubMed  Google Scholar 

  48. Zheng Y, Zhang C, Croucher DR, Soliman MA, St-Denis N, Pasculescu A, Taylor L, Tate SA, Hardy WR, Colwill K, Dai AY, Bagshaw R, Dennis JW, Gingras AC, Daly RJ, Pawson T (2013) Temporal regulation of EGF signalling networks by the scaffold protein Shc1. Nature 499(7457):166–171. doi:10.1038/nature12308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Sapra P, Betts A, Boni J (2013) Preclinical and clinical pharmacokinetic/pharmacodynamic considerations for antibody-drug conjugates. Expert Rev Clin Pharmacol 6(5):541–555. doi:10.1586/17512433.2013.827405

    Article  CAS  PubMed  Google Scholar 

  50. Burris HA 3rd, Rugo HS, Vukelja SJ, Vogel CL, Borson RA, Limentani S, Tan-Chiu E, Krop IE, Michaelson RA, Girish S, Amler L, Zheng M, Chu YW, Klencke B, O’Shaughnessy JA (2011) Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy. J Clin Oncol 29(4):398–405. doi:10.1200/JCO.2010.29.5865

    Article  CAS  PubMed  Google Scholar 

  51. Barginear MF, John V, Budman DR (2013) Trastuzumab-DM1: a clinical update of the novel antibody-drug conjugate for HER2-overexpressing breast cancer. Mol Med 18:1473–1479. doi:10.2119/molmed.2012.00302

    PubMed  Google Scholar 

  52. Senter PD (2009) Potent antibody drug conjugates for cancer therapy. Curr Opin Chem Biol 13(3):235–244. doi:10.1016/j.cbpa.2009.03.023

    Article  CAS  PubMed  Google Scholar 

  53. Opdam FL, Guchelaar HJ, Beijnen JH, Schellens JH (2012) Lapatinib for advanced or metastatic breast cancer. Oncologist 17(4):536–542. doi:10.1634/theoncologist.2011-0461

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Xia W, Mullin RJ, Keith BR, Liu LH, Ma H, Rusnak DW, Owens G, Alligood KJ, Spector NL (2002) Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways. Oncogene 21(41):6255–6263. doi:10.1038/sj.onc.1205794

    Article  CAS  PubMed  Google Scholar 

  55. Ryan Q, Ibrahim A, Cohen MH, Johnson J, Ko CW, Sridhara R, Justice R, Pazdur R (2008) FDA drug approval summary: lapatinib in combination with capecitabine for previously treated metastatic breast cancer that overexpresses HER-2. Oncologist 13(10):1114–1119. doi:10.1634/theoncologist.2008-0816

    Article  CAS  PubMed  Google Scholar 

  56. Cameron D (2007) Lapatinib plus capecitabine in patients with HER2-positive advanced breast cancer. Clin Adv Hematol Oncol 5(6):456–458

    PubMed  Google Scholar 

  57. Riemsma R, Forbes CA, Amonkar MM, Lykopoulos K, Diaz JR, Kleijnen J, Rea DW (2012) Systematic review of lapatinib in combination with letrozole compared with other first-line treatments for hormone receptor positive(HR+) and HER2+ advanced or metastatic breast cancer(MBC). Curr Med Res Opin 28(8):1263–1279. doi:10.1185/03007995.2012.707643

    Article  CAS  PubMed  Google Scholar 

  58. Finn RS, Press MF, Dering J, Arbushites M, Koehler M, Oliva C, Williams LS, Di Leo A (2009) Estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 (HER2), and epidermal growth factor receptor expression and benefit from lapatinib in a randomized trial of paclitaxel with lapatinib or placebo as first-line treatment in HER2-negative or unknown metastatic breast cancer. J Clin Oncol 27(24):3908–3915. doi:10.1200/JCO.2008.18.1925

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Burstein HJ, Storniolo AM, Franco S, Forster J, Stein S, Rubin S, Salazar VM, Blackwell KL (2008) A phase II study of lapatinib monotherapy in chemotherapy-refractory HER2-positive and HER2-negative advanced or metastatic breast cancer. Ann Oncol 19(6):1068–1074. doi:10.1093/annonc/mdm601

    Article  CAS  PubMed  Google Scholar 

  60. Di Leo A, Gomez HL, Aziz Z, Zvirbule Z, Bines J, Arbushites MC, Guerrera SF, Koehler M, Oliva C, Stein SH, Williams LS, Dering J, Finn RS, Press MF (2008) Phase III, double-blind, randomized study comparing lapatinib plus paclitaxel with placebo plus paclitaxel as first-line treatment for metastatic breast cancer. J Clin Oncol 26(34):5544–5552. doi:10.1200/JCO.2008.16.2578

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Johnston S, Pippen J Jr, Pivot X, Lichinitser M, Sadeghi S, Dieras V, Gomez HL, Romieu G, Manikhas A, Kennedy MJ, Press MF, Maltzman J, Florance A, O’Rourke L, Oliva C, Stein S, Pegram M (2009) Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol 27(33):5538–5546. doi:10.1200/JCO.2009.23.3734

    Article  CAS  PubMed  Google Scholar 

  62. Press MF, Finn RS, Cameron D, Di Leo A, Geyer CE, Villalobos IE, Santiago A, Guzman R, Gasparyan A, Ma Y, Danenberg K, Martin AM, Williams L, Oliva C, Stein S, Gagnon R, Arbushites M, Koehler MT (2008) HER-2 gene amplification, HER-2 and epidermal growth factor receptor mRNA and protein expression, and lapatinib efficacy in women with metastatic breast cancer. Clin Cancer Res 14(23):7861–7870. doi:10.1158/1078-0432.CCR-08-1056

    Article  CAS  PubMed  Google Scholar 

  63. Rexer BN, Ghosh R, Narasanna A, Estrada MV, Chakrabarty A, Song Y, Engelman JA, Arteaga CL (2013) Human breast cancer cells harboring a gatekeeper T798M mutation in HER2 overexpress EGFR ligands and are sensitive to dual inhibition of EGFR and HER2. Clin Cancer Res 19(19):5390–5401. doi:10.1158/1078-0432.CCR-13-1038

    Article  CAS  PubMed  Google Scholar 

  64. Puglisi F, Minisini AM, De Angelis C, Arpino G (2012) Overcoming treatment resistance in HER2-positive breast cancer: potential strategies. Drugs 72(9):1175–1193. doi:10.2165/11634000-000000000-00000

    Article  CAS  PubMed  Google Scholar 

  65. Liu T, Yacoub R, Taliaferro-Smith LD, Sun SY, Graham TR, Dolan R, Lobo C, Tighiouart M, Yang L, Adams A, O’Regan RM (2011) Combinatorial effects of lapatinib and rapamycin in triple-negative breast cancer cells. Mol Cancer Ther 10(8):1460–1469. doi:10.1158/1535-7163.MCT-10-0925

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Corkery B, Crown J, Clynes M, O’Donovan N (2009) Epidermal growth factor receptor as a potential therapeutic target in triple-negative breast cancer. Ann Oncol 20(5):862–867. doi:10.1093/annonc/mdn710

    Article  CAS  PubMed  Google Scholar 

  67. Baselga J, Albanell J, Ruiz A, Lluch A, Gascon P, Guillem V, Gonzalez S, Sauleda S, Marimon I, Tabernero JM, Koehler MT, Rojo F (2005) Phase II and tumor pharmacodynamic study of gefitinib in patients with advanced breast cancer. J Clin Oncol 23(23):5323–5333. doi:10.1200/JCO.2005.08.326

    Article  CAS  PubMed  Google Scholar 

  68. Bruns CJ, Solorzano CC, Harbison MT, Ozawa S, Tsan R, Fan D, Abbruzzese J, Traxler P, Buchdunger E, Radinsky R, Fidler IJ (2000) Blockade of the epidermal growth factor receptor signaling by a novel tyrosine kinase inhibitor leads to apoptosis of endothelial cells and therapy of human pancreatic carcinoma. Cancer Res 60(11):2926–2935

    CAS  PubMed  Google Scholar 

  69. Ciardiello F, Caputo R, Bianco R, Damiano V, Fontanini G, Cuccato S, De Placido S, Bianco AR, Tortora G (2001) Inhibition of growth factor production and angiogenesis in human cancer cells by ZD1839 (Iressa), a selective epidermal growth factor receptor tyrosine kinase inhibitor. Clin Cancer Res 7(5):1459–1465

    CAS  PubMed  Google Scholar 

  70. Hirata A, Ogawa S, Kometani T, Kuwano T, Naito S, Kuwano M, Ono M (2002) ZD1839 (Iressa) induces antiangiogenic effects through inhibition of epidermal growth factor receptor tyrosine kinase. Cancer Res 62(9):2554–2560

    CAS  PubMed  Google Scholar 

  71. Perrotte P, Matsumoto T, Inoue K, Kuniyasu H, Eve BY, Hicklin DJ, Radinsky R, Dinney CP (1999) Anti-epidermal growth factor receptor antibody C225 inhibits angiogenesis in human transitional cell carcinoma growing orthotopically in nude mice. Clin Cancer Res 5(2):257–265

    CAS  PubMed  Google Scholar 

  72. Dickler MN, Rugo HS, Eberle CA, Brogi E, Caravelli JF, Panageas KS, Boyd J, Yeh B, Lake DE, Dang CT, Gilewski TA, Bromberg JF, Seidman AD, D’Andrea GM, Moasser MM, Melisko M, Park JW, Dancey J, Norton L, Hudis CA (2008) A phase II trial of erlotinib in combination with bevacizumab in patients with metastatic breast cancer. Clin Cancer Res 14(23):7878–7883. doi:10.1158/1078-0432.CCR-08-0141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Montagna E, Cancello G, Bagnardi V, Pastrello D, Dellapasqua S, Perri G, Viale G, Veronesi P, Luini A, Intra M, Calleri A, Rampinelli C, Goldhirsch A, Bertolini F, Colleoni M (2012) Metronomic chemotherapy combined with bevacizumab and erlotinib in patients with metastatic HER2-negative breast cancer: clinical and biological activity. Clin Breast Cancer 12(3):207–214. doi:10.1016/j.clbc.2012.03.008

    Article  CAS  PubMed  Google Scholar 

  74. Hinck AP, Mueller TD, Springer TA (2016) Structural biology and evolution of the TGF-beta family. Cold Spring Harb Perspect Biol 8(12). doi:10.1101/cshperspect.a022103

  75. Massague J (2012) TGFbeta signalling in context. Nat Rev Mol Cell Biol 13(10):616–630. doi:10.1038/nrm3434

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70

    Article  CAS  PubMed  Google Scholar 

  77. Blobe GC, Schiemann WP, Lodish HF (2000) Role of transforming growth factor beta in human disease. N Engl J Med 342(18):1350–1358. doi:10.1056/NEJM200005043421807

    Article  CAS  PubMed  Google Scholar 

  78. Cheung SY, Boey YJ, Koh VC, Thike AA, Lim JC, Iqbal J, Tan PH (2015) Role of epithelial-mesenchymal transition markers in triple-negative breast cancer. Breast Cancer Res Treat 152(3):489–498. doi:10.1007/s10549-015-3485-1

    Article  CAS  PubMed  Google Scholar 

  79. Akhurst RJ, Hata A (2012) Targeting the TGFbeta signalling pathway in disease. Nat Rev Drug Discov 11(10):790–811. doi:10.1038/nrd3810

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Delolme F, Anastasi C, Alcaraz LB, Mendoza V, Vadon-Le Goff S, Talantikite M, Capomaccio R, Mevaere J, Fortin L, Mazzocut D, Damour O, Zanella-Cleon I, Hulmes DJ, Overall CM, Valcourt U, Lopez-Casillas F, Moali C (2015) Proteolytic control of TGF-beta co-receptor activity by BMP-1/tolloid-like proteases revealed by quantitative iTRAQ proteomics. Cellular and molecular life sciences : CMLS 72(5):1009–1027. doi:10.1007/s00018-014-1733-x

    Article  CAS  PubMed  Google Scholar 

  81. Derynck R, Akhurst RJ, Balmain A (2001) TGF-beta signaling in tumor suppression and cancer progression. Nat Genet 29(2):117–129. doi:10.1038/ng1001-117

    Article  CAS  PubMed  Google Scholar 

  82. Elliott RL, Blobe GC (2005) Role of transforming growth factor Beta in human cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 23(9):2078–2093. doi:10.1200/JCO.2005.02.047

    Article  CAS  Google Scholar 

  83. Fenig E, Kanfi Y, Wang Q, Beery E, Livnat T, Wasserman L, Lilling G, Yahalom J, Wieder R, Nordenberg J (2001) Role of transforming growth factor beta in the growth inhibition of human breast cancer cells by basic fibroblast growth factor. Breast Cancer Res Treat 70(1):27–37

    Article  CAS  PubMed  Google Scholar 

  84. Li C, Guo B, Bernabeu C, Kumar S (2001) Angiogenesis in breast cancer: the role of transforming growth factor beta and CD105. Microsc Res Tech 52(4):437–449. doi:10.1002/1097-0029(20010215)52:4<437::AID-JEMT1029>3.0.CO;2-G

    Article  CAS  PubMed  Google Scholar 

  85. Wilson TJ, Nannuru KC, Futakuchi M, Singh RK (2010) Cathepsin G-mediated enhanced TGF-beta signaling promotes angiogenesis via upregulation of VEGF and MCP-1. Cancer Lett 288(2):162–169. doi:10.1016/j.canlet.2009.06.035

    Article  CAS  PubMed  Google Scholar 

  86. Chen W, Zhou S, Mao L, Zhang H, Sun D, Zhang J, Li J, Tang JH (2016) Crosstalk between TGF-beta signaling and miRNAs in breast cancer metastasis. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 37(8):10011–10019. doi:10.1007/s13277-016-5060-8

    Article  CAS  Google Scholar 

  87. Amankulor NM, Hambardzumyan D, Pyonteck SM, Becher OJ, Joyce JA, Holland EC (2009) Sonic hedgehog pathway activation is induced by acute brain injury and regulated by injury-related inflammation. The Journal of neuroscience : the official journal of the Society for Neuroscience 29(33):10299–10308. doi:10.1523/JNEUROSCI.2500-09.2009

    Article  CAS  Google Scholar 

  88. Herbertz S, Sawyer JS, Stauber AJ, Gueorguieva I, Driscoll KE, Estrem ST, Cleverly AL, Desaiah D, Guba SC, Benhadji KA, Slapak CA, Lahn MM (2015) Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta signaling pathway. Drug Des Devel Ther 9:4479–4499. doi:10.2147/DDDT.S86621

    PubMed  PubMed Central  Google Scholar 

  89. Tang Y, Yang X, Friesel RE, Vary CP, Liaw L (2011) Mechanisms of TGF-beta-induced differentiation in human vascular smooth muscle cells. J Vasc Res 48(6):485–494. doi:10.1159/000327776

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Hawinkels LJ, Garcia de Vinuesa A, Ten Dijke P (2013) Activin receptor-like kinase 1 as a target for anti-angiogenesis therapy. Expert Opin Investig Drugs 22(11):1371–1383. doi:10.1517/13543784.2013.837884

    Article  CAS  PubMed  Google Scholar 

  91. Kano MR, Bae Y, Iwata C, Morishita Y, Yashiro M, Oka M, Fujii T, Komuro A, Kiyono K, Kaminishi M, Hirakawa K, Ouchi Y, Nishiyama N, Kataoka K, Miyazono K (2007) Improvement of cancer-targeting therapy, using nanocarriers for intractable solid tumors by inhibition of TGF-beta signaling. Proc Natl Acad Sci U S A 104(9):3460–3465. doi:10.1073/pnas.0611660104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Liu Z, Kobayashi K, van Dinther M, van Heiningen SH, Valdimarsdottir G, van Laar T, Scharpfenecker M, Lowik CW, Goumans MJ, Ten Dijke P, Pardali E (2009) VEGF and inhibitors of TGFbeta type-I receptor kinase synergistically promote blood-vessel formation by inducing alpha5-integrin expression. J Cell Sci 122(Pt 18):3294–3302. doi:10.1242/jcs.048942

    Article  CAS  PubMed  Google Scholar 

  93. Jin CH, Krishnaiah M, Sreenu D, Subrahmanyam VB, Rao KS, Lee HJ, Park SJ, Park HJ, Lee K, Sheen YY, Kim DK (2014) Discovery of N-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2 -yl)methyl)-2-fluoroaniline (EW-7197): a highly potent, selective, and orally bioavailable inhibitor of TGF-beta type I receptor kinase as cancer immunotherapeutic/antifibrotic agent. J Med Chem 57(10):4213–4238. doi:10.1021/jm500115w

    Article  CAS  PubMed  Google Scholar 

  94. Son JY, Park SY, Kim SJ, Lee SJ, Park SA, Kim MJ, Kim SW, Kim DK, Nam JS, Sheen YY (2014) EW-7197, a novel ALK-5 kinase inhibitor, potently inhibits breast to lung metastasis. Mol Cancer Ther 13(7):1704–1716. doi:10.1158/1535-7163.MCT-13-0903

    Article  CAS  PubMed  Google Scholar 

  95. Wrana JL, Attisano L, Carcamo J, Zentella A, Doody J, Laiho M, Wang XF, Massague J (1992) TGF beta signals through a heteromeric protein kinase receptor complex. Cell 71(6):1003–1014

    Article  CAS  PubMed  Google Scholar 

  96. Wieser R, Wrana JL, Massague J (1995) GS domain mutations that constitutively activate T beta R-I, the downstream signaling component in the TGF-beta receptor complex. EMBO J 14(10):2199–2208

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Leof EB, Proper JA, Goustin AS, Shipley GD, DiCorleto PE, Moses HL (1986) Induction of c-sis mRNA and activity similar to platelet-derived growth factor by transforming growth factor beta: a proposed model for indirect mitogenesis involving autocrine activity. Proc Natl Acad Sci U S A 83(8):2453–2457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Kim DK, Kim J, Park HJ (2004) Synthesis and biological evaluation of novel 2-pyridinyl-[1,2,3]triazoles as inhibitors of transforming growth factor beta 1 type 1 receptor. Bioorg Med Chem Lett 14(10):2401–2405. doi:10.1016/j.bmcl.2004.03.024

    CAS  PubMed  Google Scholar 

  99. Sawyer JS, Anderson BD, Beight DW, Campbell RM, Jones ML, Herron DK, Lampe JW, McCowan JR, McMillen WT, Mort N, Parsons S, Smith EC, Vieth M, Weir LC, Yan L, Zhang F, Yingling JM (2003) Synthesis and activity of new aryl- and heteroaryl-substituted pyrazole inhibitors of the transforming growth factor-beta type I receptor kinase domain. J Med Chem 46(19):3953–3956. doi:10.1021/jm0205705

    Article  CAS  PubMed  Google Scholar 

  100. Li HY, McMillen WT, Heap CR, McCann DJ, Yan L, Campbell RM, Mundla SR, King CH, Dierks EA, Anderson BD, Britt KS, Huss KL, Voss MD, Wang Y, Clawson DK, Yingling JM, Sawyer JS (2008) Optimization of a dihydropyrrolopyrazole series of transforming growth factor-beta type I receptor kinase domain inhibitors: discovery of an orally bioavailable transforming growth factor-beta receptor type I inhibitor as antitumor agent. J Med Chem 51(7):2302–2306. doi:10.1021/jm701199p

    Article  CAS  PubMed  Google Scholar 

  101. Peng SB, Yan L, Xia X, Watkins SA, Brooks HB, Beight D, Herron DK, Jones ML, Lampe JW, McMillen WT, Mort N, Sawyer JS, Yingling JM (2005) Kinetic characterization of novel pyrazole TGF-beta receptor I kinase inhibitors and their blockade of the epithelial-mesenchymal transition. Biochemistry 44(7):2293–2304. doi:10.1021/bi048851x

    Article  CAS  PubMed  Google Scholar 

  102. Muraoka-Cook RS, Shin I, Yi JY, Easterly E, Barcellos-Hoff MH, Yingling JM, Zent R, Arteaga CL (2006) Activated type I TGFbeta receptor kinase enhances the survival of mammary epithelial cells and accelerates tumor progression. Oncogene 25(24):3408–3423. doi:10.1038/sj.onc.1208964

    Article  CAS  PubMed  Google Scholar 

  103. Morris JC, Tan AR, Olencki TE, Shapiro GI, Dezube BJ, Reiss M, Hsu FJ, Berzofsky JA, Lawrence DP (2014) Phase I study of GC1008 (fresolimumab): a human anti-transforming growth factor-beta (TGFbeta) monoclonal antibody in patients with advanced malignant melanoma or renal cell carcinoma. PLoS One 9(3):e90353. doi:10.1371/journal.pone.0090353

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Lonning S, Mannick J, McPherson JM (2011) Antibody targeting of TGF-beta in cancer patients. Curr Pharm Biotechnol 12(12):2176–2189

    Article  CAS  PubMed  Google Scholar 

  105. Trachtman H, Fervenza FC, Gipson DS, Heering P, Jayne DR, Peters H, Rota S, Remuzzi G, Rump LC, Sellin LK, Heaton JP, Streisand JB, Hard ML, Ledbetter SR, Vincenti F (2011) A phase 1, single-dose study of fresolimumab, an anti-TGF-beta antibody, in treatment-resistant primary focal segmental glomerulosclerosis. Kidney Int 79(11):1236–1243. doi:10.1038/ki.2011.33

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Stevenson JP, Kindler HL, Papasavvas E, Sun J, Jacobs-Small M, Hull J, Schwed D, Ranganathan A, Newick K, Heitjan DF, Langer CJ, McPherson JM, Montaner LJ, Albelda SM (2013) Immunological effects of the TGFbeta-blocking antibody GC1008 in malignant pleural mesothelioma patients. Oncoimmunology 2(8):e26218. doi:10.4161/onci.26218

    Article  PubMed  PubMed Central  Google Scholar 

  107. Goetz R, Mohammadi M (2013) Exploring mechanisms of FGF signalling through the lens of structural biology. Nat Rev Mol Cell Biol 14(3):166–180. doi:10.1038/nrm3528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Beenken A, Mohammadi M (2009) The FGF family: biology, pathophysiology and therapy. Nat Rev Drug Discov 8(3):235–253. doi:10.1038/nrd2792

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Trueb B (2011) Biology of FGFRL1, the fifth fibroblast growth factor receptor. Cell Mol Life Sci 68(6):951–964

    Article  CAS  PubMed  Google Scholar 

  110. Turner N, Grose R (2010) Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer 10(2):116–129. doi:10.1038/nrc2780

    Article  CAS  PubMed  Google Scholar 

  111. Helsten T, Elkin S, Arthur E, Tomson BN, Carter J, Kurzrock R (2016) The FGFR landscape in cancer: analysis of 4,853 tumors by next-generation sequencing. Clin Cancer Res 22(1):259–267

    Article  CAS  PubMed  Google Scholar 

  112. Giacomini A, Chiodelli P, Matarazzo S, Rusnati M, Presta M, Ronca R (2016) Blocking the FGF/FGFR system as a “two-compartment” antiangiogenic/antitumor approach in cancer therapy. Pharmacol Res 107:172–185. doi:10.1016/j.phrs.2016.03.024

    Article  CAS  PubMed  Google Scholar 

  113. Theillet C, Adelaide J, Louason G, Bonnet-Dorion F, Jacquemier J, Adnane J, Longy M, Katsaros D, Sismondi P, Gaudray P (1993) FGFRI and PLAT genes and DNA amplification at 8p 12 in breast and ovarian cancers. Genes Chromosom Cancer 7(4):219–226

    Article  CAS  PubMed  Google Scholar 

  114. Reis-Filho JS, Simpson PT, Turner NC, Lambros MB, Jones C, Mackay A, Grigoriadis A, Sarrio D, Savage K, Dexter T (2006) FGFR1 emerges as a potential therapeutic target for lobular breast carcinomas. Clin Cancer Res 12(22):6652–6662

    Article  CAS  PubMed  Google Scholar 

  115. Turner N, Pearson A, Sharpe R, Lambros M, Geyer F, Lopez-Garcia MA, Natrajan R, Marchio C, Iorns E, Mackay A, Gillett C, Grigoriadis A, Tutt A, Reis-Filho JS, Ashworth A (2010) FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer Res 70(5):2085–2094. doi:10.1158/0008-5472.CAN-09-3746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Elsheikh SE, Green AR, Lambros MB, Turner NC, Grainge MJ, Powe D, Ellis IO, Reis-Filho JS (2007) FGFR1 amplification in breast carcinomas: a chromogenic in situ hybridisation analysis. Breast Cancer Res 9(2):R23

    Article  CAS  Google Scholar 

  117. Turner N, Lambros MB, Horlings HM, Pearson A, Sharpe R, Natrajan R, Geyer FC, van Kouwenhove M, Kreike B, Mackay A (2010) Integrative molecular profiling of triple negative breast cancers identifies amplicon drivers and potential therapeutic targets. Oncogene 29(14):2013–2023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Bane AL, Pinnaduwage D, Colby S, Bull SB, O’Malley FP, Andrulis IL (2009) Expression profiling of familial breast cancers demonstrates higher expression of FGFR2 in BRCA2-associated tumors. Breast Cancer Res Treat 117(1):183–191

    Article  CAS  PubMed  Google Scholar 

  119. Sugihara H, Ishimoto T, Yasuda T, Izumi D, Eto K, Sawayama H, Miyake K, Kurashige J, Imamura Y, Hiyoshi Y, Iwatsuki M, Iwagami S, Baba Y, Sakamoto Y, Miyamoto Y, Yoshida N, Watanabe M, Takamori H, Baba H (2015) Cancer-associated fibroblast-derived CXCL12 causes tumor progression in adenocarcinoma of the esophagogastric junction. Med Oncol 32(6):618. doi:10.1007/s12032-015-0618-7

    Article  PubMed  CAS  Google Scholar 

  120. Gee JM, Robertson JF, Ellis IO, Nicholson RI (2001) Phosphorylation of ERK1/2 mitogen-activated protein kinase is associated with poor response to anti-hormonal therapy and decreased patient survival in clinical breast cancer. Int J Cancer 95(4):247–254

    Article  CAS  PubMed  Google Scholar 

  121. Dallol A, Buhmeida A, Merdad A, Al-Maghrabi J, Gari MA, Abu-Elmagd MM, Elaimi A, Assidi M, Chaudhary AG, Abuzenadah AM, Nedjadi T, Ermiah E, Alkhayyat SS, Al-Qahtani MH (2015) Frequent methylation of the KLOTHO gene and overexpression of the FGFR4 receptor in invasive ductal carcinoma of the breast. Tumor Biol 36(12):9677–9683. doi:10.1007/s13277-015-3733-3

    Article  CAS  Google Scholar 

  122. Dey JH, Bianchi F, Voshol J, Bonenfant D, Oakeley EJ, Hynes NE (2010) Targeting fibroblast growth factor receptors blocks PI3K/AKT signaling, induces apoptosis, and impairs mammary tumor outgrowth and metastasis. Cancer Res 70(10):4151–4162. doi:10.1158/0008-5472.CAN-09-4479

    Article  CAS  PubMed  Google Scholar 

  123. Thomas AP, Theoclitou ME, Buttar D, Ruston L, Wrigley G, Dennis M, Rudge DA, Coleman T, Smith R, Gavine PR, Klinowska T, Mooney L, Brooks N (2012) The discovery of AZD4547: an orally bioavailable, potent and selective N-(5-Pyrazolyl)benzamide FGFR1-3 inhibitor. Cancer Res 72. doi:10.1158/1538-7445.AM2012-3912

  124. Gayine PR, Mooney L, Kilgour E, Thomas AP, Al-Kadhimi K, Beck S, Coleman T, Baker D, Mellor MJ, Brooks NAN, Klinowska T (2011) Characterization of AZD4547: an orally bioavailable, potent and selective inhibitor of FGFR tyrosine kinases 1, 2 and 3. Cancer Res 71. doi:10.1158/1538-7445.AM2011-3568

  125. Gavine PR, Mooney L, Kilgour E, Thomas AP, Al-Kadhimi K, Beck S, Rooney C, Coleman T, Baker D, Mellor MJ, Brooks AN, Klinowska T (2012) AZD4547: an orally bioavailable, potent, and selective inhibitor of the fibroblast growth factor receptor tyrosine kinase family. Cancer Res 72(8):2045–2056. doi:10.1158/0008-5472.CAN-11-3034

    Article  CAS  PubMed  Google Scholar 

  126. Liu L, Ye TH, Han YP, Song H, Zhang YK, Xia Y, Wang NY, Xiong Y, Song XJ, Zhu YX, Li de L, Zeng J, Ran K, Peng CT, Wei YQ, Yu LT (2014) Reductions in myeloid-derived suppressor cells and lung metastases using AZD4547 treatment of a metastatic murine breast tumor model. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 33(3):633–645. doi:10.1159/000358640

    Article  CAS  Google Scholar 

  127. Andre F, Ranson M, Dean E, Varga A, van der Noll R, Stockman PK, Ghiorghiu D, Kilgour E, Smith PD, Macpherson M, Lawrence P, Hastie A, Schellens JHM (2013) Results of a phase I study of AZD4547, an inhibitor of fibroblast growth factor receptor (FGFR), in patients with advanced solid tumors. Cancer Res 73(8). doi:10.1158/1538-7445.AM2013-LB-145

  128. Smyth EC, Turner NC, Peckitt C, Pearson A, Brown G, Chua S, Gillbanks A, Johnston SRD, Tarazona N, Cutts R, Kilgour E, Rooney C, Smith NR, Sumpter KA, Ajaz MA, Thomas AL, Watkins D, Chau I, Popat S, Cunningham D (2015) Phase II multicenter proof of concept study of AZD4547 in FGFR amplified tumours. J Clin Oncol 33(15)

    Google Scholar 

  129. Angibaud PR, Mevellec L, Saxty G, Adelinet C, Akkari R, Berdini V, Bonnet P, Bourgeois M, Bourdrez X, Cleasby A, Colombel H, Csoka I, Embrechts W, Freyne E, Gilissen R, Jovcheva E, King P, Lacrampe J, Lardeau D, Ligny Y, Mcclue S, Meerpoel L, Newell DR, Page M, Papanikos A, Pasquier E, Pilatte I, Poncelet V, Querolle O, Rees DC, Rich S, Roux B, Sement E, Simonnet Y, Squires M, Tronel V, Verhulst T, Vialard J, Willems M, Woodhead SJ, Wroblowski B, Murray CW, Perera T (2014) Discovery of JNJ-42756493, a potent fibroblast growth factor receptor (FGFR) inhibitor using a fragment based approach. Cancer Res 74(19). doi:10.1158/1538-7445.AM2014-4748

  130. Perera T, Jovcheva E, Vialard J, Verhulst T, Esser N, Wroblowski B, Gilissen R, Freyne E, King P, Platero S, Querolle O, Mevellec L, Murray C, Fazal L, Saxty G, Ward G, Squires M, Thompson N, Newell D, Angibaud P (2014) JNJ-42756493 is an inhibitor of FGFR-1, 2, 3 and 4 with nanomolar affinity for targeted therapy. Cancer Res 74(19). doi:10.1158/1538-7445.AM2014-1738

  131. Dienstmann R, Bahleda R, Adamo B, Rodon J, Varga A, Gazzah A, Platero S, Smit H, Perera T, Zhong B, Stuyckens K, Elsayed Y, Takimoto C, Peddareddigari V, Tabernero J, Luo FR, Soria JC (2014) First in human study of JNJ-42756493, a potent pan fibroblast growth factor receptor (FGFR) inhibitor in patients with advanced solid tumors. Cancer Res 74(19). doi:10.1158/1538-7445.AM2014-CT325

  132. Bahleda R, Dienstmann R, Adamo B, Gazzah A, Infante JR, Zhong B, Platero SJ, Smit H, Perera T, Stuyckens K, Bussolari J, Poddareddigari V, Soria JC, Luo FR, Tabernero J (2014) Phase 1 study of JNJ-42756493, a pan-fibroblast growth factor receptor (FGFR) inhibitor, in patients with advanced solid tumors. J Clin Oncol 32(15)

    Google Scholar 

  133. Guagnano V, Furet P, Spanka C, Bordas V, Le Douget M, Stamm C, Brueggen J, Jensen MR, Schnell C, Schmid H, Wartmann M, Berghausen J, Drueckes P, Zimmerlin A, Bussiere D, Murray J, Graus Porta D (2011) Discovery of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamin o]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), a potent and selective inhibitor of the fibroblast growth factor receptor family of receptor tyrosine kinase. J Med Chem 54(20):7066–7083. doi:10.1021/jm2006222

  134. Sequist LV, Cassier P, Varga A, Tabernero J, Schellens JH, Delord JP, LoRusso P, Camidge DR, Medina MH, Schuler M, Campone M, Tian GG, Wong S, Corral J, Isaacs R, Sen SK, Porta DG, Kulkarni SG, Lefebvre C, Wolf J (2014) Phase I study of BGJ398, a selective pan-FGFR inhibitor in genetically preselected advanced solid tumors. Cancer Res 74(19). doi:10.1158/1538-7445.AM2014-CT326

  135. Leroith D, Roberts CT (1993) Insulin-like growth-factors and their receptors in normal physiology and pathological states. J Pediatr Endocrinol 6(3–4):251–255

    CAS  PubMed  Google Scholar 

  136. LeRoith D, King G, Flier JS (1997) Insulin-like growth factors. N Engl J Med 336(9):633–640

    Article  CAS  Google Scholar 

  137. Oates AJ, Schumaker LM, Jenkins SB, Pearce AA, DaCosta SA, Arun B, Ellis MJ (1998) The mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R), a putative breast tumor suppressor gene. Breast Cancer Res Treat 47(3):269–281

    Article  CAS  PubMed  Google Scholar 

  138. Tao Y, Pinzi V, Bourhis J, Deutsch E (2007) Mechanisms of disease: signaling of the insulin-like growth factor 1 receptor pathway--therapeutic perspectives in cancer. Nat Clin Pract Oncol 4(10):591–602. doi:10.1038/ncponc0934

    Article  CAS  PubMed  Google Scholar 

  139. Mauro L, Naimo GD, Ricchio E, Panno ML, Ando S (2015) Cross-talk between Adiponectin and IGF-IR in breast cancer. Front Oncol 5:157. doi:10.3389/fonc.2015.00157

    Article  PubMed  PubMed Central  Google Scholar 

  140. Danielsen A, Larsen E, Gammeltoft S (1990) Chromaffin cells express two types of insulin-like growth factor receptors. Brain Res 518(1–2):95–100

    Article  CAS  PubMed  Google Scholar 

  141. Sachdev D, Yee D (2007) Disrupting insulin-like growth factor signaling as a potential cancer therapy. Mol Cancer Ther 6(1):1–12. doi:10.1158/1535-7163.MCT-06-0080

    Article  CAS  PubMed  Google Scholar 

  142. Denduluri SK, Idowu O, Wang Z, Liao Z, Yan Z, Mohammed MK, Ye J, Wei Q, Wang J, Zhao L, Luu HH (2015) Insulin-like growth factor (IGF) signaling in tumorigenesis and the development of cancer drug resistance. Genes & diseases 2(1):13–25. doi:10.1016/j.gendis.2014.10.004

    Article  CAS  Google Scholar 

  143. Papa V, Gliozzo B, Clark GM, McGuire WL, Moore D, Fujita-Yamaguchi Y, Vigneri R, Goldfine ID, Pezzino V (1993) Insulin-like growth factor-I receptors are overexpressed and predict a low risk in human breast cancer. Cancer Res 53(16):3736–3740

    CAS  PubMed  Google Scholar 

  144. Yerushalmi R, Gelmon KA, Leung S, Gao D, Cheang M, Pollak M, Turashvili G, Gilks BC, Kennecke H (2012) Insulin-like growth factor receptor (IGF-1R) in breast cancer subtypes. Breast Cancer Res Treat 132(1):131–142. doi:10.1007/s10549-011-1529-8

    Article  CAS  PubMed  Google Scholar 

  145. Lu YH, Zi XL, Zhao YH, Mascarenhas D, Pollak M (2001) Insulin-like growth factor-I receptor signaling and resistance to trastuzumab (Herceptin). J Nat Cancer Inst 93(24):1852–1857 10.1093/jnci/93.24.1852

  146. Gallagher EJ, LeRoith D (2011) Minireview: IGF, insulin, and cancer. Endocrinology 152(7):2546–2551. doi:10.1210/en.2011-0231

    Article  CAS  PubMed  Google Scholar 

  147. Brahmkhatri VP, Prasanna C, Atreya HS (2015) Insulin-like growth factor system in cancer: novel targeted therapies. Biomed Res Int 2015:538019. doi:10.1155/2015/538019

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  148. Cohen BD, Baker DA, Soderstrom C, Tkalcevic G, Rossi AM, Miller PE, Tengowski MW, Wang F, Gualberto A, Beebe JS, Moyer JD (2005) Combination therapy enhances the inhibition of tumor growth with the fully human anti-type 1 insulin-like growth factor receptor monoclonal antibody CP-751,871. Clinical cancer research : an official journal of the American Association for Cancer Research 11(5):2063–2073. doi:10.1158/1078-0432.CCR-04-1070

    Article  CAS  Google Scholar 

  149. Chakraborty AK, Zerillo C, DiGiovanna MP (2015) In vitro and in vivo studies of the combination of IGF1R inhibitor figitumumab (CP-751,871) with HER2 inhibitors trastuzumab and neratinib. Breast Cancer Res Treat 152(3):533–544. doi:10.1007/s10549-015-3504-2

    Article  CAS  PubMed  Google Scholar 

  150. Beltran PJ, Mitchell P, Chung YA, Cajulis E, Lu J, Belmontes B, Ho J, Tsai MM, Zhu M, Vonderfecht S, Baserga R, Kendall R, Radinsky R, Calzone FJ (2009) AMG 479, a fully human anti-insulin-like growth factor receptor type I monoclonal antibody, inhibits the growth and survival of pancreatic carcinoma cells. Mol Cancer Ther 8(5):1095–1105. doi:10.1158/1535-7163.MCT-08-1171

    Article  CAS  PubMed  Google Scholar 

  151. Beltran PJ, Chung YA, Moody G, Mitchell P, Cajulis E, Vonderfecht S, Kendall R, Radinsky R, Calzone FJ (2011) Efficacy of ganitumab (AMG 479), alone and in combination with rapamycin, in Ewing’s and osteogenic sarcoma models. J Pharmacol Exp Ther 337(3):644–654. doi:10.1124/jpet.110.178400

    Article  CAS  PubMed  Google Scholar 

  152. Mendivil A, Zhou C, Cantrell LA, Gehrig PA, Malloy KM, Blok LJ, Burger CW, Bae-Jump VL (2011) AMG 479, a novel IGF-1-R antibody, inhibits endometrial cancer cell proliferation through disruption of the PI3K/Akt and MAPK pathways. Reprod Sci 18(9):832–841. doi:10.1177/1933719111398501

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Cao ZA, Pinzon-Ortiz M, Chen Y, Li X, Beltran PJ, Gansert J, Peters M, Schlegel R, Schumacher KM, Huang A (2014) Targeting PIK3CA mutant breast cancer with the combination of PIK3CA-specific inhibitor, BYL719, and IGF1-R antibody, ganitumab. AACR

    Google Scholar 

  154. Murakami H, Doi T, Yamamoto N, Watanabe J, Boku N, Fuse N, Yoshino T, Ohtsu A, Otani S, Shibayama K, Takubo T, Loh E (2012) Phase 1 study of ganitumab (AMG 479), a fully human monoclonal antibody against the insulin-like growth factor receptor type I (IGF1R), in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol 70(3):407–414. doi:10.1007/s00280-012-1924-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Tolcher AW, Sarantopoulos J, Patnaik A, Papadopoulos K, Lin CC, Rodon J, Murphy B, Roth B, McCaffery I, Gorski KS, Kaiser B, Zhu M, Deng H, Friberg G, Puzanov I (2009) Phase I, pharmacokinetic, and pharmacodynamic study of AMG 479, a fully human monoclonal antibody to insulin-like growth factor receptor 1. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 27(34):5800–5807. doi:10.1200/JCO.2009.23.6745

    Article  CAS  Google Scholar 

  156. Robertson JFR, Ferrero J-M, Bourgeois H, Kennecke H, de Boer RH, Jacot W, McGreivy J, Suzuki S, Zhu M, McCaffery I, Loh E, Gansert JL, Kaufman PA (2013) Ganitumab with either exemestane or fulvestrant for postmenopausal women with advanced, hormone-receptor-positive breast cancer: a randomised, controlled, double-blind, phase 2 trial. Lancet Oncol 14(3):228–235. doi:10.1016/s1470-2045(13)70026-3

    Article  CAS  PubMed  Google Scholar 

  157. Yee D, Paoloni M, van’t Veer L, Sanil A, Yau C, Forero A, Chien A, Wallace A, Moulder S, Albain K (2017) Abstract P6–11-04: the evaluation of ganitumab/metformin plus standard neoadjuvant therapy in high-risk breast cancer: results from the I-SPY 2 trial. AACR

    Google Scholar 

  158. Burtrum D, Zhu Z, Lu D, Anderson DM, Prewett M, Pereira DS, Bassi R, Abdullah R, Hooper AT, Koo H, Jimenez X, Johnson D, Apblett R, Kussie P, Bohlen P, Witte L, Hicklin DJ, Ludwig DL (2003) A fully human monoclonal antibody to the insulin-like growth factor I receptor blocks ligand-dependent signaling and inhibits human tumor growth in vivo. Cancer Res 63(24):8912–8921

    CAS  PubMed  Google Scholar 

  159. Gradishar WJ, Yardley DA, Layman R, Sparano JA, Chuang E, Northfelt DW, Schwartz GN, Youssoufian H, Tang S, Novosiadly R, Forest A, Nguyen TS, Cosaert J, Grebennik D, Haluska P (2016) Clinical and translational results of a phase II, randomized trial of an anti-IGF-1R (Cixutumumab) in women with breast cancer that progressed on endocrine therapy. Clin Cancer Res 22(2):301–309. doi:10.1158/1078-0432.CCR-15-0588

    Article  CAS  PubMed  Google Scholar 

  160. Haluska P, Bernath AM, Ballman KV, Dueck AC, Linden HM, Goetz MP, Northfelt DW, Hou X, Tenner KS, Tienchaiananda P (2014) Randomized phase II trial of capecitabine and lapatinib with or without cixutumumab in patients with HER2+ breast cancer previously treated with trastuzumab and an anthracycline and/or a taxane: NCCTG N0733 (alliance). American Society of Clinical Oncology

    Google Scholar 

  161. Lee JW, Soung YH, Kim SY, Lee HW, Park WS, Nam SW, Kim SH, Lee JY, Yoo NJ, Lee SH (2005) PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcinomas. Oncogene 24(8):1477–1480. doi:10.1038/sj.onc.1208304

    Article  CAS  PubMed  Google Scholar 

  162. Bachman KE, Argani P, Samuels Y, Silliman N, Ptak J, Szabo S, Konishi H, Karakas B, Blair BG, Lin C, Peters BA, Velculescu VE, Park BH (2004) The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol Ther 3(8):772–775

    Article  CAS  PubMed  Google Scholar 

  163. Bachman KE, Argani P, Samuels Y, Silliman N, Ptak J, Szabo S, Konishi H, Karakas B, Blair BG, Lin C, Peters BA, Velculescu VE, Park BH (2005) The PIK3CA gene is mutated with high frequency in human breast cancers (vol 3, pg 772, 2004). Cancer Biol Ther 4(2):133–133

    Article  CAS  Google Scholar 

  164. Sun SY, Rosenberg LM, Wang XR, Zhou ZM, Yue P, Fu H, Khuri FR (2005) Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res 65(16):7052–7058. doi:10.1158/0008-5472.CAN-05-0917

    Article  CAS  PubMed  Google Scholar 

  165. Shi YJ, Yan HJ, Frost P, Gera J, Lichtenstein A (2005) Mammalian target of rapamycin inhibitors activate the AKT kinase in multiple myeloma cells by up-regulating the insulin-like growth factor receptor/insulin receptor substrate-1/phosphatidylinositol 3-kinase cascade. Mol Cancer Ther 4(10):1533–1540. doi:10.1158/1535-7163.MCT-05-0068

    Article  CAS  PubMed  Google Scholar 

  166. Wan X, Harkavy B, Shen N, Grohar P, Helman LJ (2007) Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism. Oncogene 26(13):1932–1940. doi:10.1038/sj.onc.1209990

    Article  CAS  PubMed  Google Scholar 

  167. Ma CX, Suman VJ, Goetz M, Haluska P, Moynihan T, Nanda R, Olopade O, Pluard T, Guo ZF, Chen HX, Erlichman C, Ellis MJ, Fleming GF (2013) A phase I trial of the IGF-1R antibody Cixutumumab in combination with temsirolimus in patients with metastatic breast cancer. Breast Cancer Res Treat 139(1):145–153. doi:10.1007/s10549-013-2528-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Schnitzer T, Kuenkele K-P, Rebers F, Van Vugt M, Klein C, Lanzendoerfer M, Mundigl O, Parren P, van de Winkel J, Schumacher R (2006) 214 POSTER characterization of a recombinant, fully human monoclonal antibody directed against the human insulin-like growth factor-1 receptor. EJC Suppl 4(12):66–67

    Article  Google Scholar 

  169. Kurzrock R, Patnaik A, Aisner J, Warren T, Leong S, Benjamin R, Eckhardt SG, Eid JE, Greig G, Habben K, McCarthy CD, Gore L (2010) A phase I study of weekly R1507, a human monoclonal antibody insulin-like growth factor-I receptor antagonist, in patients with advanced solid tumors. Clin Cancer Res 16(8):2458–2465. doi:10.1158/1078-0432.CCR-09-3220

    Article  CAS  PubMed  Google Scholar 

  170. Mahadevan D, Sutton GR, Arteta-Bulos R, Bowden CJ, Miller PJ, Swart RE, Walker MS, Haluska P, Munster PN, Marshall J, Hamid O, Kurzrock R (2014) Phase 1b study of safety, tolerability and efficacy of R1507, a monoclonal antibody to IGF-1R in combination with multiple standard oncology regimens in patients with advanced solid malignancies. Cancer Chemother Pharmacol 73(3):467–473. doi:10.1007/s00280-013-2372-x

    Article  CAS  PubMed  Google Scholar 

  171. Hutcheson IR, Pumford SL, Barrow D, Frankel SR, Nicholson RI (2009) Abstract B125: antiproliferative and anti-invasive effect of the novel anti-IGF-1R monoclonal antibody R1507 in endocrine-responsive and-resistant breast cancer cell lines. AACR

    Google Scholar 

  172. Sanchez C, Crowder R, Phommaly C, Ellis M (2009) The effect of the IGF1R antibody R1507 on ER positive breast cancer cell lines growth and survival. AACR

    Google Scholar 

  173. Maloney EK, McLaughlin JL, Dagdigian NE, Garrett LM, Connors KM, Zhou X-M, Blättler WA, Chittenden T, Singh R (2003) An anti-insulin-like growth factor I receptor antibody that is a potent inhibitor of cancer cell proliferation. Cancer Res 63(16):5073–5083

    CAS  PubMed  Google Scholar 

  174. Descamps G, Wuilleme-Toumi S, Trichet V, Venot C, Debussche L, Hercend T, Collette M, Robillard N, Bataille R, Amiot M (2006) CD45neg but not CD45pos human myeloma cells are sensitive to the inhibition of IGF-1 signaling by a murine anti-IGF-1R monoclonal antibody, mAVE1642. J Immunol 177(6):4218–4223. doi:10.4049/jimmunol.177.6.4218

    Article  CAS  PubMed  Google Scholar 

  175. Geoerger B, Brasme JF, Daudigeos-Dubus E, Opolon P, Venot C, Debussche L, Vrignaud P, Vassal G (2010) Anti-insulin-like growth factor 1 receptor antibody EM164 (murine AVE1642) exhibits anti-tumour activity alone and in combination with temozolomide against neuroblastoma. Eur J Cancer 46(18):3251–3262. doi:10.1016/j.ejca.2010.06.005

    Article  CAS  PubMed  Google Scholar 

  176. Descamps G, Gomez-Bougie P, Venot C, Moreau P, Bataille R, Amiot M (2009) A humanised anti-IGF-1R monoclonal antibody (AVE1642) enhances Bortezomib-induced apoptosis in myeloma cells lacking CD45. Br J Cancer 100(2):366–369. doi:10.1038/sj.bjc.6604839

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Soria JC, Massard C, Lazar V, Ozoux ML, Mery-Mignard D, Deslandes A, Tolcher AW (2013) A dose finding, safety and pharmacokinetic study of AVE1642, an anti-insulin-like growth factor-1 receptor (IGF-1R/CD221) monoclonal antibody, administered as a single agent and in combination with docetaxel in patients with advanced solid tumours. Eur J Cancer 49(8):1799–1807. doi:10.1016/j.ejca.2013.01.003

    Article  CAS  PubMed  Google Scholar 

  178. Macaulay VM, Middleton MR, Protheroe AS, Tolcher A, Dieras V, Sessa C, Bahleda R, Blay JY, LoRusso P, Mery-Mignard D, Soria JC (2013) Phase I study of humanized monoclonal antibody AVE1642 directed against the type 1 insulin-like growth factor receptor (IGF-1R), administered in combination with anticancer therapies to patients with advanced solid tumors. Annals of oncology : official journal of the European Society for Medical Oncology 24(3):784–791. doi:10.1093/annonc/mds511

    Article  CAS  Google Scholar 

  179. Goetsch L, Gonzalez A, Leger O, Beck A, Pauwels PJ, Haeuw JF, Corvaia N (2005) A recombinant humanized anti-insulin-like growth factor receptor type I antibody (h7C10) enhances the antitumor activity of vinorelbine and anti-epidermal growth factor receptor therapy against human cancer xenografts. Int J Cancer 113(2):316–328. doi:10.1002/ijc.20543

    Article  CAS  PubMed  Google Scholar 

  180. Goetsch I, Gonzalez A, Beck A, Haeuw J, Corvaia N (2004) 286 generation of a recombinant humanized anti-insulin-like growth factor receptor type I antibody (h7C10) with an antitumor activity in a variety of human cancer xenograft models. EJC Suppl 2(8):87–88

    Article  Google Scholar 

  181. Scartozzi M, Bianconi M, Maccaroni E, Giampieri R, Berardi R, Cascinu S (2010) Dalotuzumab, a recombinant humanized mAb targeted against IGFR1 for the treatment of cancer. Curr Opin Mol Ther 12(3):361–371

    CAS  PubMed  Google Scholar 

  182. Di Cosimo S, Sathyanarayanan S, Bendell JC, Cervantes A, Stein MN, Brana I, Roda D, Haines BB, Zhang T, Winter CG, Jha S, Xu Y, Frazier J, Klinghoffer RA, Leighton-Swayze A, Song Y, Ebbinghaus S, Baselga J (2015) Combination of the mTOR inhibitor ridaforolimus and the anti-IGF1R monoclonal antibody dalotuzumab: preclinical characterization and phase I clinical trial. Clinical cancer research : an official journal of the American Association for Cancer Research 21(1):49–59. doi:10.1158/1078-0432.CCR-14-0940

    Article  CAS  Google Scholar 

  183. Becker MA, Hou X, Tienchaianada P, Haines BB, Harrington SC, Weroha SJ, Sathyanarayanan S, Haluska P (2016) Ridaforolimus (MK-8669) synergizes with Dalotuzumab (MK-0646) in hormone-sensitive breast cancer. BMC Cancer 16(1):814. doi:10.1186/s12885-016-2847-3

    Article  PubMed  PubMed Central  Google Scholar 

  184. Lu B, Blum J, Cortes J, Rugo H, Swanton C, Eaton L, Song Y, Zhang T, Ebbinghaus S, Baselga J (2011) OT3–01-16: a phase 2 study of Ridaforolimus (RIDA) and Dalotuzumab (DALO) in estrogen receptor positive (ER+) breast cancer. AACR

    Google Scholar 

  185. Baselga J, Morales S, Awada A, Blum J, Tan A, Ewertz M, Cortes J, Moy B, Ruddy K, Haddad T (2013) Abstract P2–16-04: a phase 2 study of ridaforolimus (RIDA) and dalotuzumab (DALO) in estrogen receptor positive (ER+) breast cancer. AACR

    Google Scholar 

  186. Baselga J, Morales SM, Awada A, Blum JL, Tan AR, Ewertz M, Cortes J, Moy B, Ruddy KJ, Haddad T, Ciruelos EM, Vuylsteke P, Ebbinghaus S, Im E, Eaton L, Pathiraja K, Gause C, Mauro D, Jones MB, Rugo HS (2017) A phase II study of combined ridaforolimus and dalotuzumab compared with exemestane in patients with estrogen receptor-positive breast cancer. Breast Cancer Res Treat:1–10. doi:10.1007/s10549-017-4199-3

  187. Rugo HS, Tredan O, Ro J, Morales S, Musolino A, Afonso N, Ferreira M, Park KH, Cortes J, Tan AR (2015) Abstract PD5–1: results from the phase 2 trial of ridaforolimus, dalotuzumab, and exemestane compared to ridaforolimus and exemestane in advanced breast cancer. AACR

    Google Scholar 

  188. Wittman MD, Carboni JM, Yang Z, Lee FY, Antman M, Attar R, Balimane P, Chang C, Chen C, Discenza L, Frennesson D, Gottardis MM, Greer A, Hurlburt W, Johnson W, Langley DR, Li A, Li J, Liu P, Mastalerz H, Mathur A, Menard K, Patel K, Sack J, Sang X, Saulnier M, Smith D, Stefanski K, Trainor G, Velaparthi U, Zhang G, Zimmermann K, Vyas DM (2009) Discovery of a 2,4-disubstituted pyrrolo[1,2-f][1,2,4]triazine inhibitor (BMS-754807) of insulin-like growth factor receptor (IGF-1R) kinase in clinical development. J Med Chem 52(23):7360–7363. doi:10.1021/jm900786r

    Article  CAS  PubMed  Google Scholar 

  189. Carboni JM, Wittman M, Yang Z, Lee F, Greer A, Hurlburt W, Hillerman S, Cao C, Cantor GH, Dell-John J, Chen C, Discenza L, Menard K, Li A, Trainor G, Vyas D, Kramer R, Attar RM, Gottardis MM (2009) BMS-754807, a small molecule inhibitor of insulin-like growth factor-1R/IR. Mol Cancer Ther 8(12):3341–3349. doi:10.1158/1535-7163.MCT-09-0499

    Article  CAS  PubMed  Google Scholar 

  190. Hou X, Huang F, Macedo LF, Harrington SC, Reeves KA, Greer A, Finckenstein FG, Brodie A, Gottardis MM, Carboni JM, Haluska P (2011) Dual IGF-1R/InsR inhibitor BMS-754807 synergizes with hormonal agents in treatment of estrogen-dependent breast cancer. Cancer Res 71(24):7597–7607. doi:10.1158/0008-5472.CAN-11-1080

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Du, J., Yu, Y., Zhan, J., Zhang, H. (2017). Targeted Therapies Against Growth Factor Signaling in Breast Cancer. In: Song, E., Hu, H. (eds) Translational Research in Breast Cancer. Advances in Experimental Medicine and Biology, vol 1026. Springer, Singapore. https://doi.org/10.1007/978-981-10-6020-5_6

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