Role of the NOTCH Signaling Pathway in Head and Neck Cancer

  • Adrian D. Schubert
  • Fernando T. Zamuner
  • Nyall R. LondonJr
  • Alex Zhavoronkov
  • Ranee Mehra
  • Mohammad O. Hoque
  • Atul Bedi
  • Rajani Ravi
  • Elana J. Fertig
  • David Sidransky
  • Daria A. Gaykalova
  • Evgeny IzumchenkoEmail author
Part of the Current Cancer Research book series (CUCR)


The NOTCH signaling cascade has been implicated in multiple cellular functions, such as cell proliferation, differentiation, and survival. Dysregulation of the NOTCH pathway is associated with the progression of several types of malignant tumors, including head and neck squamous cell carcinoma (HNSCC). Accumulating data suggest that NOTCH is one of the most frequently altered pathways in HNSCC. Given the importance of NOTCH signaling in regulating tumor cell behavior, several NOTCH-targeted strategies are currently being developed and tested in preclinical and clinical settings. However, the precise role of the NOTCH pathway in head and neck malignancies remains incompletely defined and controversial. In most tumor types, NOTCH1 has been reported as an oncogene. However, early characterization of the genomic landscape found that inactivating mutations of NOTCH1 frequently occur in HNSCC, suggesting that NOTCH1 is a tumor suppressor. More recent evidence indicates that NOTCH signaling may be activated in a subset of HNSCC tumors, similar to other tumor types, indicating a more complex function in HNSCC. This overview will summarize the evidence for oncogenic and tumor suppressor roles of the NOTCH signaling pathway in HNSCC, discuss recent studies that aid in interpretation of these contradictory findings, and describe potential therapeutic opportunities and future directions.


Head and neck cancer Notch receptors Notch signaling pathway y-secretase inhibitor Mutation Oncogene Tumor suppressor 


Conflicts of Interest

The authors declare no conflict of interest.


  1. 1.
    Torre LA, et al. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108.PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5–29.PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Califano J, et al. Unknown primary head and neck squamous cell carcinoma: molecular identification of the site of origin. J Natl Cancer Inst. 1999;91(7):599–604.PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Cianchetti M, et al. Diagnostic evaluation of squamous cell carcinoma metastatic to cervical lymph nodes from an unknown head and neck primary site. Laryngoscope. 2009;119(12):2348–54.PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Nagao T, et al. Oral cancer screening as an integral part of general health screening in Tokoname City, Japan. J Med Screen. 2000;7(4):203–8.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Subramanian S, et al. Cost-effectiveness of oral cancer screening: results from a cluster randomized controlled trial in India. Bull World Health Organ. 2009;87(3):200–6.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Agrawal N, et al. Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science. 2011;333(6046):1154–7.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Pickering CR, et al. Integrative genomic characterization of oral squamous cell carcinoma identifies frequent somatic drivers. Cancer Discov. 2013;3(7):770–81.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Stransky N, et al. The mutational landscape of head and neck squamous cell carcinoma. Science. 2011;333(6046):1157–60.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Cancer Genome Atlas N. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015;517(7536):576–82.CrossRefGoogle Scholar
  11. 11.
    Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: cell fate control and signal integration in development. Science. 1999;284(5415):770–6.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Hori K, Sen A, Artavanis-Tsakonas S. Notch signaling at a glance. J Cell Sci. 2013;126(Pt 10):2135–40.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Ellisen LW, et al. TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell. 1991;66(4):649–61.PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Ntziachristos P, et al. From fly wings to targeted cancer therapies: a centennial for notch signaling. Cancer Cell. 2014;25(3):318–34.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Sun W, et al. Activation of the NOTCH pathway in head and neck cancer. Cancer Res. 2014;74(4):1091–104.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Liu YF, et al. Somatic mutations and genetic variants of NOTCH1 in head and neck squamous cell carcinoma occurrence and development. Sci Rep. 2016;6:24014.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Capaccione KM, Pine SR. The Notch signaling pathway as a mediator of tumor survival. Carcinogenesis. 2013;34(7):1420–30.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Wang Z, et al. Emerging role of Notch in stem cells and cancer. Cancer Lett. 2009;279(1):8–12.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Zeng Q, et al. Crosstalk between tumor and endothelial cells promotes tumor angiogenesis by MAPK activation of Notch signaling. Cancer Cell. 2005;8(1):13–23.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Gu F, et al. Expression of Stat3 and Notch1 is associated with cisplatin resistance in head and neck squamous cell carcinoma. Oncol Rep. 2010;23(3):671–6.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Ferrando AA. The role of NOTCH1 signaling in T-ALL. Hematology Am Soc Hematol Educ Program. 2009;2009:353–61.Google Scholar
  22. 22.
    Song X, et al. Common and complex Notch1 mutations in Chinese oral squamous cell carcinoma. Clin Cancer Res. 2014;20:701–10.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Izumchenko E, et al. Notch1 mutations are drivers of oral tumorigenesis. Cancer Prev Res (Phila). 2015;8(4):277–86.CrossRefGoogle Scholar
  24. 24.
    Egloff AM, Grandis JR. Molecular pathways: context-dependent approaches to Notch targeting as cancer therapy. Clin Cancer Res. 2012;18(19):5188–95.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Louvi A, Artavanis-Tsakonas S. Notch and disease: a growing field. Semin Cell Dev Biol. 2012;23(4):473–80.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Hijioka H, et al. Upregulation of Notch pathway molecules in oral squamous cell carcinoma. Int J Oncol. 2010;36(4):817–22.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Zhang TH, et al. Activation of Notch signaling in human tongue carcinoma. J Oral Pathol Med. 2011;40(1):37–45.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Rettig EM, et al. Cleaved NOTCH1 expression pattern in head and neck squamous cell carcinoma is associated with NOTCH1 mutation, HPV status, and high-risk features. Cancer Prev Res (Phila). 2015;8(4):287–95.CrossRefGoogle Scholar
  29. 29.
    Chiorean EG, et al. A phase I first-in-human study of Enoticumab (REGN421), a fully Human Delta-like ligand 4 (Dll4) monoclonal antibody in patients with advanced solid tumors. Clin Cancer Res. 2015;21(12):2695–703.Google Scholar
  30. 30.
    Smith DC, et al. A phase I dose escalation and expansion study of the anticancer stem cell agent demcizumab (anti-DLL4) in patients with previously treated solid tumors. Clin Cancer Res. 2014;20(24):6295–303.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Takebe N, Nguyen D, Yang SX. Targeting notch signaling pathway in cancer: clinical development advances and challenges. Pharmacol Ther. 2014;141(2):140–9.PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Lee SM, et al. Phase 2 study of RO4929097, a gamma-secretase inhibitor, in metastatic melanoma: SWOG 0933. Cancer. 2015;121(3):432–40.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Diaz-Padilla I, et al. A phase Ib combination study of RO4929097, a gamma-secretase inhibitor, and temsirolimus in patients with advanced solid tumors. Investig New Drugs. 2013;31(5):1182–91.CrossRefGoogle Scholar
  34. 34.
    Locatelli MA, et al. Phase I study of the gamma secretase inhibitor PF-03084014 in combination with docetaxel in patients with advanced triple-negative breast cancer. Oncotarget. 2017;8(2):2320–8.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Papayannidis C, et al. A phase 1 study of the novel gamma-secretase inhibitor PF-03084014 in patients with T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma. Blood Cancer J. 2015;5:e350.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Messersmith WA, et al. A phase I, dose-finding study in patients with advanced solid malignancies of the oral gamma-secretase inhibitor PF-03084014. Clin Cancer Res. 2015;21(1):60–7.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Andersson ER, Lendahl U. Therapeutic modulation of Notch signalling – are we there yet? Nat Rev Drug Discov. 2014;13(5):357–78.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Diaz-Padilla I, et al. A phase II study of single-agent RO4929097, a gamma-secretase inhibitor of Notch signaling, in patients with recurrent platinum-resistant epithelial ovarian cancer: a study of the Princess Margaret, Chicago and California phase II consortia. Gynecol Oncol. 2015;137(2):216–22.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Piha-Paul SA, et al. Results of a phase 1 trial combining ridaforolimus and MK-0752 in patients with advanced solid tumours. Eur J Cancer. 2015;51(14):1865–73.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Yuan X, et al. Notch signaling: an emerging therapeutic target for cancer treatment. Cancer Lett. 2015;369(1):20–7.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Shimizu K, et al. Functional diversity among Notch1, Notch2, and Notch3 receptors. Biochem Biophys Res Commun. 2002;291(4):775–9.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Kopan R, Ilagan MX. The canonical Notch signaling pathway: unfolding the activation mechanism. Cell. 2009;137(2):216–33.PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Chillakuri CR, et al. Notch receptor-ligand binding and activation: insights from molecular studies. Semin Cell Dev Biol. 2012;23(4):421–8.PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Pei Z, Baker NE. Competition between Delta and the Abruptex domain of Notch. BMC Dev Biol. 2008;8:4.PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    de Celis JF, Bray SJ. The Abruptex domain of Notch regulates negative interactions between Notch, its ligands and fringe. Development. 2000;127(6):1291–302.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Malecki MJ, et al. Leukemia-associated mutations within the NOTCH1 heterodimerization domain fall into at least two distinct mechanistic classes. Mol Cell Biol. 2006;26(12):4642–51.PubMedCrossRefPubMedCentralGoogle Scholar
  47. 47.
    Choi SH, et al. Conformational locking upon cooperative assembly of notch transcription complexes. Structure. 2012;20(2):340–9.PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Arnett KL, et al. Structural and mechanistic insights into cooperative assembly of dimeric Notch transcription complexes. Nat Struct Mol Biol. 2010;17(11):1312–7.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Sulis ML, et al. NOTCH1 extracellular juxtamembrane expansion mutations in T-ALL. Blood. 2008;112(3):733–40.PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Weng AP, et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science. 2004;306(5694):269–71.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Baldus CD, et al. Prognostic implications of NOTCH1 and FBXW7 mutations in adult acute T-lymphoblastic leukemia. Haematologica. 2009;94(10):1383–90.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Fiuza UM, Arias AM. Cell and molecular biology of Notch. J Endocrinol. 2007;194(3):459–74.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Bray SJ. Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol. 2006;7(9):678–89.PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Chesworth BM, et al. Reliability and validity of two versions of the upper extremity functional index. Physiother Can. 2014;66(3):243–53.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Zhang M, et al. Does Notch play a tumor suppressor role across diverse squamous cell carcinomas? Cancer Med. 2016;5(8):2048–60.PubMedCrossRefPubMedCentralGoogle Scholar
  56. 56.
    Yap LF, et al. The opposing roles of NOTCH signalling in head and neck cancer: a mini review. Oral Dis. 2015;21(7):850–7.PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Nowell CS, Radtke F. Notch as a tumour suppressor. Nat Rev Cancer. 2017;17(3):145–59.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Ranganathan P, Weaver KL, Capobianco AJ. Notch signalling in solid tumours: a little bit of everything but not all the time. Nat Rev Cancer. 2011;11(5):338–51.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Joo YH, et al. Relationship between vascular endothelial growth factor and Notch1 expression and lymphatic metastasis in tongue cancer. Otolaryngol Head Neck Surg. 2009;140(4):512–8.PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Wang W-M, et al. Epidermal growth factor receptor inhibition reduces angiogenesis via hypoxia-inducible factor-1α and Notch1 in head neck squamous cell carcinoma. PLoS One. 2015;10(2):e0119723.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Troy JD, et al. Expression of EGFR, VEGF, and NOTCH1 suggest differences in tumor angiogenesis in HPV-positive and HPV-negative head and neck squamous cell carcinoma. Head Neck Pathol. 2013;7(4):344–55.PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Leethanakul C, et al. Distinct pattern of expression of differentiation and growth-related genes in squamous cell carcinomas of the head and neck revealed by the use of laser capture microdissection and cDNA arrays. Oncogene. 2000;19(March):3220–4.PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Ha PK, et al. A transcriptional progression model for head and neck cancer. Clin Cancer Res. 2003;9(8):3058–64.PubMedPubMedCentralGoogle Scholar
  64. 64.
    Zhang ZP, et al. Correlation of Notch1 expression and activation to cisplatin-sensitivity of head and neck squamous cell carcinoma. Ai Zheng. 2009;28(2):100–3.PubMedPubMedCentralGoogle Scholar
  65. 65.
    Yoshida R, et al. The pathological significance of Notch1 in oral squamous cell carcinoma. Lab Investig. 2013;93(10):1068–81.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Snijders AM, et al. Rare amplicons implicate frequent deregulation of cell fate specification pathways in oral squamous cell carcinoma. Oncogene. 2005;24(26):4232–42.PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Li D, et al. Notch1 overexpression associates with poor prognosis in human laryngeal squamous cell carcinoma. Ann Otol Rhinol Laryngol. 2014;123(10):705–10.PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Lin JT, et al. Association of high levels of Jagged-1 and Notch-1 expression with poor prognosis in head and neck cancer. Ann Surg Oncol. 2010;17(11):2976–83.PubMedCrossRefPubMedCentralGoogle Scholar
  69. 69.
    Inamura N, et al. Notch1 regulates invasion and metastasis of head and neck squamous cell carcinoma by inducing EMT through c-Myc. Auris Nasus Larynx. 2016;44(4):447–57.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Dai MY, et al. Downregulation of Notch1 induces apoptosis and inhibits cell proliferation and metastasis in laryngeal squamous cell carcinoma. Oncol Rep. 2015;34(6):3111–9.PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Weaver AN, et al. Notch Signaling activation is associated with patient mortality and increased FGF1-mediated invasion in squamous cell carcinoma of the oral cavity. Mol Cancer Res. 2016;14(9):883–91.PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Zhao ZL, et al. NOTCH1 inhibition enhances the efficacy of conventional chemotherapeutic agents by targeting head neck cancer stem cell. Sci Rep. 2016;6:24704.PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Gaykalova DA, et al. Integrative computational analysis of transcriptional and epigenetic alterations implicates DTX1 as a putative tumor suppressor gene in HNSCC. Oncotarget. 2017;8(9):15349–63.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Stylianou S, Clarke RB, Brennan K. Aberrant activation of notch signaling in human breast cancer. Cancer Res. 2006;66(3):1517–25.PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Xie XQ, et al. Dysregulation of mRNA profile in cisplatin-resistant gastric cancer cell line SGC7901. World J Gastroenterol. 2017;23(7):1189–202.PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Zhang Z, Filho MS, Nor JE. The biology of head and neck cancer stem cells. Oral Oncol. 2012;48(1):1–9.PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Lee SH, et al. Notch1 signaling contributes to stemness in head and neck squamous cell carcinoma. Lab Invest. 2016;96(5):508–16.PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Lee SH, et al. Epigallocatechin-3-gallate attenuates head and neck cancer stem cell traits through suppression of Notch pathway. Eur J Cancer. 2013;49(15):3210–8.PubMedCrossRefPubMedCentralGoogle Scholar
  79. 79.
    Upadhyay P, et al. Notch pathway activation is essential for maintenance of stem-like cells in early tongue cancer. Oncotarget. 2016;7(31):50437–49.PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Yu X, et al. Notch signaling activation in human embryonic stem cells is required for embryonic, but not trophoblastic, lineage commitment. Cell Stem Cell. 2008;2(5):461–71.PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Shi G, Jin Y. Role of Oct4 in maintaining and regaining stem cell pluripotency. Stem Cell Res Ther. 2010;1(5):39.PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Neville BW, Day TA. Oral cancer and precancerous lesions. CA Cancer J Clin. 2002;52(4):195–215.PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Haya-Fernandez MC, et al. The prevalence of oral leukoplakia in 138 patients with oral squamous cell carcinoma. Oral Dis. 2004;10(6):346–8.PubMedCrossRefPubMedCentralGoogle Scholar
  84. 84.
    Mehanna HM, et al. Treatment and follow-up of oral dysplasia – a systematic review and meta-analysis. Head Neck. 2009;31(12):1600–9.PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Silverman S Jr, Gorsky M, Lozada F. Oral leukoplakia and malignant transformation. A follow-up study of 257 patients. Cancer. 1984;53(3):563–8.PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Lee SH, et al. TNFalpha enhances cancer stem cell-like phenotype via Notch-Hes1 activation in oral squamous cell carcinoma cells. Biochem Biophys Res Commun. 2012;424(1):58–64.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Gokulan R, Halagowder D. Expression pattern of Notch intracellular domain (NICD) and Hes-1 in preneoplastic and neoplastic human oral squamous epithelium: their correlation with c-Myc, clinicopathological factors and prognosis in oral cancer. Med Oncol. 2014;31(8):126.PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    Rettig EM, et al. Whole-genome sequencing of salivary gland adenoid cystic carcinoma. Cancer Prev Res (Phila). 2016;9(4):265–74.Google Scholar
  89. 89.
    Ferrarotto R, et al. Activating NOTCH1 mutations define a distinct subgroup of patients with adenoid cystic carcinoma who have poor prognosis, propensity to bone and liver metastasis, and potential responsiveness to Notch1 inhibitors. J Clin Oncol. 2017;35(3):352–60.PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Yao J, et al. Gamma-secretase inhibitors exerts antitumor activity via down-regulation of Notch and nuclear factor kappa B in human tongue carcinoma cells. Oral Dis. 2007;13(6):555–63.PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Wu CX, et al. Notch inhibitor PF-03084014 inhibits hepatocellular carcinoma growth and metastasis via suppression of cancer stemness due to reduced activation of Notch1-Stat3. Mol Cancer Ther. 2017;16(8):1531–43.PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    Gavai AV, et al. Discovery of clinical candidate BMS-906024: a potent pan-notch inhibitor for the treatment of leukemia and solid tumors. ACS Med Chem Lett. 2015;6(5):523–7.PubMedCrossRefPubMedCentralGoogle Scholar
  93. 93.
    Mohamed AA, et al. Synergistic activity with NOTCH inhibition and androgen ablation in ERG-positive prostate cancer cells. Mol Cancer Res. 2017;15(10):1308–17.PubMedCrossRefPubMedCentralGoogle Scholar
  94. 94.
    Barat S, et al. Gamma-Secretase inhibitor IX (GSI) impairs concomitant activation of Notch and wnt-beta-catenin pathways in CD44+ gastric Cancer stem cells. Stem Cells Transl Med. 2017;6(3):819–29.PubMedCrossRefPubMedCentralGoogle Scholar
  95. 95.
    De Kloe GE, De Strooper B. Small molecules that inhibit Notch signaling. Methods Mol Biol. 2014;1187:311–22.PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    Pant S, et al. A first-in-human phase I study of the oral Notch inhibitor, LY900009, in patients with advanced cancer. Eur J Cancer. 2016;56:1–9.PubMedCrossRefPubMedCentralGoogle Scholar
  97. 97.
    Bossi P, Alfieri S. Investigational drugs for head and neck cancer. Expert Opin Investig Drugs. 2016;25(7):797–810.PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Kramer A, et al. Small molecules intercept Notch signaling and the early secretory pathway. Nat Chem Biol. 2013;9(11):731–8.PubMedCrossRefPubMedCentralGoogle Scholar
  99. 99.
    Borgegard T, et al. First and second generation gamma-secretase modulators (GSMs) modulate amyloid-beta (Abeta) peptide production through different mechanisms. J Biol Chem. 2012;287(15):11810–9.PubMedCrossRefPubMedCentralGoogle Scholar
  100. 100.
    Kumar R, Juillerat-Jeanneret L, Golshayan D. Notch antagonists: potential modulators of Cancer and inflammatory diseases. J Med Chem. 2016;59(17):7719–37.PubMedCrossRefPubMedCentralGoogle Scholar
  101. 101.
    Nicolas M, et al. Notch1 functions as a tumor suppressor in mouse skin. Nat Genet. 2003;33(3):416–21.PubMedCrossRefPubMedCentralGoogle Scholar
  102. 102.
    Naganuma S, et al. Notch receptor inhibition reveals the importance of cyclin D1 and Wnt signaling in invasive esophageal squamous cell carcinoma. Am J Cancer Res. 2012;2(4):459–75.PubMedPubMedCentralGoogle Scholar
  103. 103.
    Nguyen BC, et al. Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation. Genes Dev. 2006;20(8):1028–42.PubMedCrossRefPubMedCentralGoogle Scholar
  104. 104.
    Rangarajan A, et al. Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. EMBO J. 2001;20(13):3427–36.PubMedCrossRefPubMedCentralGoogle Scholar
  105. 105.
    Ohashi S, et al. NOTCH1 and NOTCH3 coordinate esophageal squamous differentiation through a CSL-dependent transcriptional network. Gastroenterology. 2010;139(6):2113–23.PubMedCrossRefPubMedCentralGoogle Scholar
  106. 106.
    Duan L, et al. Growth suppression induced by Notch1 activation involves Wnt-beta-catenin down-regulation in human tongue carcinoma cells. Biol Cell. 2006;98(8):479–90.PubMedCrossRefPubMedCentralGoogle Scholar
  107. 107.
    Jiao J, et al. Potential role of Notch1 signaling pathway in laryngeal squamous cell carcinoma cell line Hep-2 involving proliferation inhibition, cell cycle arrest, cell apoptosis, and cell migration. Oncol Rep. 2009;22(4):815–23.PubMedPubMedCentralGoogle Scholar
  108. 108.
    Sakamoto K, et al. Reduction of NOTCH1 expression pertains to maturation abnormalities of keratinocytes in squamous neoplasms. Lab Investig. 2012;92(5):688–702.PubMedCrossRefPubMedCentralGoogle Scholar
  109. 109.
    Gaykalova DA, et al. Novel insight into mutational landscape of head and neck squamous cell carcinoma. PLoS One. 2014;9(3):e93102.PubMedCrossRefPubMedCentralGoogle Scholar
  110. 110.
    Coric V, et al. Safety and tolerability of the gamma-secretase inhibitor avagacestat in a phase 2 study of mild to moderate Alzheimer disease. Arch Neurol. 2012;69(11):1430–40.PubMedCrossRefPubMedCentralGoogle Scholar
  111. 111.
    Doody RS, et al. Peripheral and central effects of gamma-secretase inhibition by semagacestat in Alzheimer's disease. Alzheimers Res Ther. 2015;7(1):36.PubMedCrossRefPubMedCentralGoogle Scholar
  112. 112.
    Radtke F, Raj K. The role of Notch in tumorigenesis: oncogene or tumour suppressor? Nat Rev Cancer. 2003;3(10):756–67.PubMedCrossRefPubMedCentralGoogle Scholar
  113. 113.
    Olsauskas-Kuprys R, Zlobin A, Osipo C. Gamma secretase inhibitors of Notch signaling. Onco Targets Ther. 2013;6:943–55.PubMedPubMedCentralGoogle Scholar
  114. 114.
    Li K, et al. Modulation of Notch signaling by antibodies specific for the extracellular negative regulatory region of NOTCH3. J Biol Chem. 2008;283(12):8046–54.PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    Aoyama K, et al. Frequent mutations in NOTCH1 ligand-binding regions in Japanese oral squamous cell carcinoma. Biochem Biophys Res Commun. 2014;452(4):980–5.PubMedCrossRefPubMedCentralGoogle Scholar
  116. 116.
    Seiwert TY, et al. Integrative and comparative genomic analysis of HPV-positive and HPV-negative head and neck squamous cell carcinomas. Clin Cancer Res. 2015;21(3):632–41.PubMedCrossRefGoogle Scholar
  117. 117.
    Zhong R, et al. Notch1 activation or loss promotes HPV-induced oral tumorigenesis. Cancer Res. 2015;75(18):3958–69.PubMedCrossRefPubMedCentralGoogle Scholar
  118. 118.
    Weijzen S, et al. HPV16 E6 and E7 oncoproteins regulate Notch-1 expression and cooperate to induce transformation. J Cell Physiol. 2003;194(3):356–62.PubMedCrossRefPubMedCentralGoogle Scholar
  119. 119.
    Talora C, et al. Specific down-modulation of Notch1 signaling in cervical cancer cells is required for sustained HPV-E6/E7 expression and late steps of malignant transformation. Genes Dev. 2002;16(17):2252–63.PubMedCrossRefPubMedCentralGoogle Scholar
  120. 120.
    Sausville EA, Burger AM. Contributions of human tumor xenografts to anticancer drug development. Cancer Res. 2006;66(7):3351–4, discussion 3354.PubMedCrossRefPubMedCentralGoogle Scholar
  121. 121.
    Izumchenko E, et al. Patient-derived xenografts as tools in pharmaceutical development. Clin Pharmacol Ther. 2016;99(6):612–21.PubMedCrossRefPubMedCentralGoogle Scholar
  122. 122.
    Kagohara L, et al. Epigenetic regulation of gene expression in cancer: techniques, resources, and analysis. Brief Funct Genomics. 2018;17(1):49–63.Google Scholar
  123. 123.
    Ozerov IV, et al. In silico Pathway Activation Network Decomposition Analysis (iPANDA) as a method for biomarker development. Nat Commun. 2016;7:13427.PubMedCrossRefPubMedCentralGoogle Scholar
  124. 124.
    Mroz EA, Rocco JW. MATH, a novel measure of intratumor genetic heterogeneity, is high in poor-outcome classes of head and neck squamous cell carcinoma. Oral Oncol. 2013;49(3):211–5.PubMedCrossRefPubMedCentralGoogle Scholar
  125. 125.
    Afsari B, Geman D, Fertig EJ. Learning dysregulated pathways in cancers from differential variability analysis. Cancer Inform. 2014;13(Suppl 5):61–7.PubMedPubMedCentralGoogle Scholar
  126. 126.
    Makarev E, et al. In silico analysis of pathways activation landscape in oral squamous cell carcinoma and oral leukoplakia. Cell Death Discov. 2017;3:17022.PubMedCrossRefPubMedCentralGoogle Scholar
  127. 127.
    Ogmundsdottir HM, Bjornsson J, Holbrook WP. Role of TP53 in the progression of pre-malignant and malignant oral mucosal lesions. A follow-up study of 144 patients. J Oral Pathol Med. 2009;38(7):565–71.PubMedCrossRefPubMedCentralGoogle Scholar
  128. 128.
    Hori K, et al. Synergy between the ESCRT-III complex and Deltex defines a ligand-independent Notch signal. J Cell Biol. 2011;195(6):1005–15.PubMedCrossRefPubMedCentralGoogle Scholar
  129. 129.
    Li JL, et al. DLL4-Notch signaling mediates tumor resistance to anti-VEGF therapy in vivo. Cancer Res. 2011;71(18):6073–83.PubMedCrossRefPubMedCentralGoogle Scholar
  130. 130.
    Doroquez DB, Rebay I. Signal integration during development: mechanisms of EGFR and Notch pathway function and cross-talk. Crit Rev Biochem Mol Biol. 2006;41(6):339–85.PubMedCrossRefPubMedCentralGoogle Scholar
  131. 131.
    Hayward P, et al. Notch modulates Wnt signalling by associating with Armadillo/beta-catenin and regulating its transcriptional activity. Development. 2005;132(8):1819–30.PubMedCrossRefPubMedCentralGoogle Scholar
  132. 132.
    Shin M, Nagai H, Sheng G. Notch mediates Wnt and BMP signals in the early separation of smooth muscle progenitors and blood/endothelial common progenitors. Development. 2009;136(4):595–603.PubMedCrossRefPubMedCentralGoogle Scholar
  133. 133.
    Blokzijl A, et al. Cross-talk between the Notch and TGF-beta signaling pathways mediated by interaction of the Notch intracellular domain with Smad3. J Cell Biol. 2003;163(4):723–8.PubMedCrossRefPubMedCentralGoogle Scholar
  134. 134.
    Kanehisa M, Goto S. KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 2000;28(1):27–30.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Adrian D. Schubert
    • 1
  • Fernando T. Zamuner
    • 1
  • Nyall R. LondonJr
    • 1
  • Alex Zhavoronkov
    • 2
  • Ranee Mehra
    • 3
  • Mohammad O. Hoque
    • 1
  • Atul Bedi
    • 1
  • Rajani Ravi
    • 1
  • Elana J. Fertig
    • 4
  • David Sidransky
    • 1
  • Daria A. Gaykalova
    • 1
  • Evgeny Izumchenko
    • 1
    Email author
  1. 1.Johns Hopkins University, School of Medicine, Department of Otolaryngology-Head & Neck Cancer ResearchBaltimoreUSA
  2. 2.Insilico Medicine, Inc., Emerging Technology Centers, Johns Hopkins University at EasternBaltimoreUSA
  3. 3.Department of OncologyJohns Hopkins University School of MedicineBaltimoreUSA
  4. 4.Johns Hopkins University, School of MedicineDepartment of Oncology-Division of Biostatistics and BioinformaticsBaltimoreUSA

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