Cancer and Metastasis Reviews

, Volume 36, Issue 3, pp 463–473 | Cite as

EGFR-targeted therapies in the post-genomic era

  • Mary Jue Xu
  • Daniel E. Johnson
  • Jennifer R. Grandis
Article
First Online:

Abstract

Over 90% of head and neck cancers overexpress the epidermal growth factor receptor (EGFR). In diverse tumor types, EGFR overexpression has been associated with poorer prognosis and outcomes. Therapies targeting EGFR include monoclonal antibodies, tyrosine kinase inhibitors, phosphatidylinositol 3-kinase (PI3K) inhibitors, and antisense gene therapy. Few EGFR-targeted therapeutics are approved for clinical use. The monoclonal antibody cetuximab is a Food and Drug Administration (FDA)-approved EGFR-targeted therapy, yet has exhibited modest benefit in clinical trials. The humanized monoclonal antibody nimotuzumab is also approved for head and neck cancers in Cuba, Argentina, Colombia, Peru, India, Ukraine, Ivory Coast, and Gabon in addition to nasopharyngeal cancers in China. Few other EGFR-targeted therapeutics for head and neck cancers have led to as significant responses as seen in lung carcinomas, for instance. Recent genome sequencing of head and neck tumors has helped identify patient subgroups with improved response to EGFR inhibitors, for example, cetuximab in patients with the KRAS-variant and the tyrosine kinase inhibitor erlotinib for tumors harboring MAPK1E322K mutations. Genome sequencing has furthermore broadened our understanding of dysregulated pathways, holding the potential to enhance the benefit derived from therapies targeting EGFR.

Keywords

EGFR Head and neck SCC Genomics Cetuximab 
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Notes

Acknowledgements

This work was supported by the National Institutes of Health grants R01 DE24728 (DEJ), P50CA097190 (DEJ and JRG), and R01 DE023685 (JRG), and American Cancer Society grant CRP-13-308-06-COUN (JRG).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Cohen, S. (1960). Purification of a nerve-growth promoting protein from the mouse salivary gland and its neuro-cytotoxic antiserum. Proceedings of the National Academy of Sciences of the United States of America, 46(3), 302–311.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Wong, A. J., Bigner, S. H., Bigner, D. D., Kinzler, K. W., Hamilton, S. R., & Vogelstein, B. (1987). Increased expression of the epidermal growth factor receptor gene in malignant gliomas is invariably associated with gene amplification. Proceedings of the National Academy of Sciences of the United States of America, 84(19), 6899–6903.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Nicholson, R. I., Gee, J. M., & Harper, M. E. (2001). EGFR and cancer prognosis. European Journal of Cancer, 37(Suppl 4), S9–15.CrossRefPubMedGoogle Scholar
  4. 4.
    Herbst, R. S. (2004). Review of epidermal growth factor receptor biology. International Journal of Radiation Oncology, Biology, Physics, 59(2 Suppl), 21–26.CrossRefPubMedGoogle Scholar
  5. 5.
    Cohen, S. (1962). Isolation of a mouse submaxillary gland protein accelerating incisor eruption and eyelid opening in the new-born animal. The Journal of Biological Chemistry, 237, 1555–1562.PubMedGoogle Scholar
  6. 6.
    Ward, C. W., & Garrett, T. P. (2001). The relationship between the L1 and L2 domains of the insulin and epidermal growth factor receptors and leucine-rich repeat modules. BMC Bioinformatics, 2, 4.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    van der Veeken, J., Oliveira, S., Schiffelers, R. M., Storm, G., van Bergen En Henegouwen, P. M., & Roovers, R. C. (2009). Crosstalk between epidermal growth factor receptor- and insulin-like growth factor-1 receptor signaling: implications for cancer therapy. Current Cancer Drug Targets, 9(6), 748–760.CrossRefPubMedGoogle Scholar
  8. 8.
    Roudabush, F. L., Pierce, K. L., Maudsley, S., Khan, K. D., & Luttrell, L. M. (2000). Transactivation of the EGF receptor mediates IGF-1-stimulated shc phosphorylation and ERK1/2 activation in COS-7 cells. Journal of Biological Chemistry, 275(29), 22583–22589.CrossRefPubMedGoogle Scholar
  9. 9.
    Ward, C. W., Hoyne, P. A., & Flegg, R. H. (1995). Insulin and epidermal growth factor receptors contain the cysteine repeat motif found in the tumor necrosis factor receptor. Proteins, 22(2), 141–153.CrossRefPubMedGoogle Scholar
  10. 10.
    Ferguson, K. M., Berger, M. B., Mendrola, J. M., Cho, H. S., Leahy, D. J., & Lemmon, M. A. (2003). EGF activates its receptor by removing interactions that autoinhibit ectodomain dimerization. Molecular Cell, 11(2), 507–517.CrossRefPubMedGoogle Scholar
  11. 11.
    Cummings, R. D., Soderquist, A. M., & Carpenter, G. (1985). The oligosaccharide moieties of the epidermal growth factor receptor in A-431 cells. Presence of complex- type N-linked chains that contain terminal N-acetylgalactosamine residues. Journal Biological Chemistry, 260(22), 11944–11952.Google Scholar
  12. 12.
    Whitson, K. B., Whitson, S. R., Red-Brewer, M. L., McCoy, A. J., Vitali, A. A., Walker, F., et al. (2005). Functional effects of glycosylation at Asn-579 of the epidermal growth factor receptor. Biochemistry, 44(45), 14920–14931.CrossRefPubMedGoogle Scholar
  13. 13.
    Yewale, C., Baradia, D., Vhora, I., Patil, S., & Misra, A. (2013). Epidermal growth factor receptor targeting in cancer: a review of trends and strategies. Biomaterials, 34(34), 8690–8707.CrossRefPubMedGoogle Scholar
  14. 14.
    Chong, C. R., & Jänne, P. A. (2013). The quest to overcome resistance to EGFR-targeted therapies in cancer. Nature Medicine, 19(11), 1389–1400.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Goldman, C. K., Kim, J., Wong, W. L., King, V., Brock, T., & Gillespie, G. Y. (1993). Epidermal growth factor stimulates vascular endothelial growth factor production by human malignant glioma cells: a model of glioblastoma multiforme pathophysiology. Molecular Biology of the Cell, 4(1), 121–133.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Sibilia, M., Kroismayr, R., Lichtenberger, B. M., Natarajan, A., Hecking, M., & Holcmann, M. (2007). The epidermal growth factor receptor: from development to tumorigenesis. Differentiation, 75(9), 770–787.CrossRefPubMedGoogle Scholar
  17. 17.
    Rubin Grandis, J., Melhem, M. F., Gooding, W. E., Day, R., Holst, V. A., Wagener, M. M., et al. (1998). Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival. Journal of the National Cancer Institute, 90(11), 824–832.CrossRefPubMedGoogle Scholar
  18. 18.
    Grandis, J. R., & Tweardy, D. J. (1993). Elevated levels of transforming growth factor alpha and epidermal growth factor receptor messenger RNA are early markers of carcinogenesis in head and neck cancer. Cancer Research, 53(15), 3579–3584.PubMedGoogle Scholar
  19. 19.
    Ang, K. K., Berkey, B. A., Tu, X., Zhang, H. Z., Katz, R., Hammond, E. H., et al. (2002). Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Research, 62(24), 7350–7356.PubMedGoogle Scholar
  20. 20.
    Temam, S., Kawaguchi, H., El-Naggar, A. K., Jelinek, J., Tang, H., Liu, D. D., et al. (2007). Epidermal growth factor receptor copy number alterations correlate with poor clinical outcome in patients with head and neck squamous cancer. Journal of Clinical Oncology, 25, 2164–2170.CrossRefPubMedGoogle Scholar
  21. 21.
    Slamon, D. J., Clark, G. M., Wong, S. G., Levin, W. J., Ullrich, A., & McGuire, W. L. (1987). Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science, 235(4785), 177–182.CrossRefPubMedGoogle Scholar
  22. 22.
    Franklin, W. A., Veve, R., Hirsch, F. R., Helfrich, B. A., & Bunn Jr., P. A. (2002). Epidermal growth factor receptor family in lung cancer and premalignancy. Seminars in Oncology, 29(1 Suppl 4), 3–14.CrossRefPubMedGoogle Scholar
  23. 23.
    Wen, Y., & Grandis, J. R. (2015). Emerging drugs for head and neck cancer. Expert Opinion on Emerging Drugs, 20(2), 313–329.CrossRefPubMedGoogle Scholar
  24. 24.
    Chen, D. J., & Nirodi, C. S. (2007). The epidermal growth factor receptor: a role in repair of radiation-induced DNA damage. Clinical Cancer Research, 13(22 Pt 1), 6555–6560.CrossRefPubMedGoogle Scholar
  25. 25.
    Bonner, J. A., Harari, P. M., Giralt, J., Azarnia, N., Shin, D. M., Cohen, R. B., et al. (2006). Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. The New England Journal of Medicine, 354(6), 567–578.CrossRefPubMedGoogle Scholar
  26. 26.
    Bonner, J. A., Harari, P. M., Giralt, J., Cohen, R. B., Jones, C. U., Sur, R. K., et al. (2010). Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncology, 11(1), 21–28.CrossRefPubMedGoogle Scholar
  27. 27.
    Vermorken, J. B., Trigo, J., Hitt, R., Koralewski, P., Diaz-Rubio, E., Rolland, F., et al. (2007). Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. Journal of Clinical Oncology, 25(16), 2171–2177.CrossRefPubMedGoogle Scholar
  28. 28.
    Vermorken, J. B., Mesia, R., Rivera, F., Remenar, E., Kawecki, A., Rottey, S., et al. (2008). Platinum-based chemotherapy plus cetuximab in head and neck cancer. The New England Journal of Medicine, 359(11), 1116–1127.CrossRefPubMedGoogle Scholar
  29. 29.
    Ang, K. K., Zhang, Q., Rosenthal, D. I., Nguyen-Tan, P. F., Sherman, E. J., Weber, R. S., et al. (2014). Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III to IV head and neck carcinoma: RTOG 0522. Journal of Clinical Oncology, 32(27), 2940–2950.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Vermorken, J. B., Stöhlmacher-Williams, J., Davidenko, I., Licitra, L., Winquist, E., Villanueva, C., et al. (2013). Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial. Lancet Oncology, 14(8), 697–710.CrossRefPubMedGoogle Scholar
  31. 31.
    Mesía, R., Henke, M., Fortin, A., Minn, H., Yunes Ancona, A. C., Cmelak, A., et al. (2015). Chemoradiotherapy with or without panitumumab in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck (CONCERT-1): a randomised, controlled, open-label phase 2 trial. Lancet Oncology, 16(2), 208–220.CrossRefPubMedGoogle Scholar
  32. 32.
    Machiels, J. P., Subramanian, S., Ruzsa, A., Repassy, G., Lifirenko, I., Flygare, A., et al. (2011). Zalutumumab plus best supportive care versus best supportive care alone in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after failure of platinum-based chemotherapy: an open-label, randomised phase 3 trial. Lancet Oncology, 12(4), 333–343.CrossRefPubMedGoogle Scholar
  33. 33.
    Rodríguez, M. O., Rivero, T. C., del Castillo, B. R., Muchuli, C. R., Bilbao, M. A., Vinageras, E. N., et al. (2010). Nimotuzumab plus radiotherapy for unresectable squamous-cell carcinoma of the head and neck. Cancer Biology & Therapy, 9(5), 343–349.CrossRefGoogle Scholar
  34. 34.
    Basavaraj, C., Sierra, P., Shivu, J., Melarkode, R., Montero, E., & Nair, P. (2010). Nimotuzumab with chemoradiation confers a survival advantage in treatment- naive head and neck tumors over expressing EGFR. Cancer Biology & Therapy, 10(7), 673–681.CrossRefGoogle Scholar
  35. 35.
    Fayette, J., Wirth, L., Oprean, C., Udrea, A., Jimeno, A., Rischin, D., et al. (2016). Randomized phase II study of duligotuzumab (MEHD7945A) vs. cetuximab in squamous cell carcinoma of the head and neck(MEHGAN study). Frontiers in Oncology, 6, 232.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Martins, R. G., Parvathaneni, U., Bauman, J. E., Sharma, A. K., Raez, L. E., Papagikos, M. A., et al. (2013). Cisplatin and radiotherapy with or without erlotinib in locally advanced squamous cell carcinoma of the head and neck: a randomized phase II trial. Journal of Clinical Oncology, 31(11), 1415–1421.CrossRefPubMedGoogle Scholar
  37. 37.
    Argiris, A., Ghebremichael, M., Gilbert, J., Lee, J. W., Sachidanandam, K., Kolesar, J. M., et al. (2013). Phase III randomized, placebo-controlled trial of docetaxel with or without gefitinib in recurrent or metastatic head and neck cancer: an Eastern Cooperative Oncology Group trial. Journal of Clinical Oncology, 31(11), 1405–1414.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Paez, J. G., Jänne, P. A., Lee, J. C., Tracy, S., Greulich, H., Gabriel, S., et al. (2004). EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science, 304(5676), 1497–1500.CrossRefPubMedGoogle Scholar
  39. 39.
    Afghahi, A., & Sledge Jr., G. W. (2015). Targeted therapy for cancer in the genomic era. Cancer Journal, 21(4), 294–298.CrossRefGoogle Scholar
  40. 40.
    Seiwert, T. Y., Fayette, J., Cupissol, D., Del Campo, J. M., Clement, P. M., Hitt, R., et al. (2014). A randomized, phase II study of afatinib versus cetuximab in metastatic or recurrent squamous cell carcinoma of the head and neck. Annals of Oncology, 25(9), 1813–1820.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Machiels, J. P., Haddad, R. I., Fayette, J., Licitra, L. F., Tahara, M., Vermorken, J. B., et al. (2015). Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial. Lancet Oncology, 16(5), 583–594.CrossRefPubMedGoogle Scholar
  42. 42.
    Harrington, K., Berrier, A., Robinson, M., Remenar, E., Housset, M., de Mendoza, F. H., et al. (2013). Randomised phase II study of oral lapatinib combined with chemoradiotherapy in patients with advanced squamous cell carcinoma of the head and neck: rationale for future randomised trials in human papilloma virus-negative disease. European Journal of Cancer, 49(7), 1609–1618.CrossRefPubMedGoogle Scholar
  43. 43.
    Harrington, K., Temam, S., Mehanna, H., D'Cruz, A., Jain, M., D'Onofrio, I., et al. (2015). Postoperative adjuvant lapatinib and concurrent chemoradiotherapy followed by maintenance lapatinib monotherapy in high-risk patients with resected squamous cell carcinoma of the head and neck: a phase III, randomized, double-blind, placebo-controlled study. Journal of Clinical Oncology, 10(33(35)), 4202–4209.CrossRefGoogle Scholar
  44. 44.
    Del Campo, J. M., Hitt, R., Sebastian, P., Carracedo, C., Lokanatha, D., Bourhis, J., et al. (2011). Effects of lapatinib monotherapy: results of a randomised phase II study in therapy-naive patients with locally advanced squamous cell carcinoma of the head and neck. British Journal of Cancer, 105(5), 618–627.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    de Souza, J. A., Davis, D. W., Zhang, Y., Khattri, A., Seiwert, T. Y., Aktolga, S., et al. (2012). A phase II study of lapatinib in recurrent/metastatic squamous cell carcinoma of the head and neck. Clinical Cancer Research, 18(8), 2336–2343.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Abdul Razak, A. R., Soulières, D., Laurie, S. A., Hotte, S. J., Singh, S., Winquist, E., et al. (2013). A phase II trial of dacomitinib, an oral pan-human EGF receptor (HER) inhibitor, as first-line treatment in recurrent and/or metastatic squamous-cell carcinoma of the head and neck. Annals of Oncology, 24(3), 761–769.CrossRefPubMedGoogle Scholar
  47. 47.
    Cancer Genome Atlas Network. (2015). Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature, 517(7536), 576–582.CrossRefGoogle Scholar
  48. 48.
    Lui, V. W., Hedberg, M. L., Li, H., Vangara, B. S., Pendleton, K., Zeng, Y., et al. (2013). Frequent mutation of the PI3K pathway in head and neck cancer defines predictive biomarkers. Cancer Discovery, 3(7), 761–769.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Soulières, D., Faivre, S., Mesía, R., Remenár, É., Li, S. H., Karpenko, A., et al. (2017). Buparlisib and paclitaxel in patients with platinum-pretreatment recurrent or metastatic squamous cell carcinoma of the head and neck (BERIL-1): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Oncology, 18(3), 323–335.CrossRefPubMedGoogle Scholar
  50. 50.
    Gleave, M. E., & Monia, B. P. (2005). Antisense therapy for cancer. Nature Reviews Cancer, 5(6), 468–479.CrossRefPubMedGoogle Scholar
  51. 51.
    Lai, S. Y., Koppikar, P., Thomas, S. M., Childs, E. E., Egloff, A. M., Seethala, R. R., et al. (2009). Intratumoral epidermal growth factor receptor antisense DNA therapy in head and neck cancer: first human application and potential antitumor mechanisms. Journal of Clinical Oncology, 27(8), 1235–1242.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Hammerman, P. S., Hayes, D. N., & Grandis, J. R. (2015). Therapeutic insights from genomic studies of head and neck squamous cell carcinomas. Cancer Discovery, 5(3), 239–244.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Stransky, N., Egloff, A. M., Tward, A. D., Kostic, A. D., Cibulskis, K., Sivachenko, A., et al. (2011). The mutational landscape of head and neck squamous cell carcinoma. Science, 333(6046), 1157–1160.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Agrawal, N., Frederick, M. J., Pickering, C. R., Bettegowda, C., Chang, K., Li, R. J., et al. (2011). Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science, 333(6046), 1154–1157.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Lawrence, M. S., Stojanov, P., Mermel, C. H., Robinson, J. T., Garraway, L. A., Golub, T. R., et al. (2014). Discovery and saturation analysis of cancer genes across 21 tumour types. Nature, 505(7484), 495–501.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Chang, M. T., Asthana, S., Gao, S. P., Lee, B. H., Chapman, J. S., Kandoth, C., et al. (2016). Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity. Nature Biotechnology, 34(2), 155–163.CrossRefPubMedGoogle Scholar
  57. 57.
    Weidhaas, J. B., Harris, J., Schaue, D., Chen, A. M., Chin, R., Axelrod, R., et al. (2016). The KRAS-variant and cetuximab response in head and neck squamous cell cancer: a secondary analysis of a randomized clinical trial. JAMA Oncology, 3(4), 483–491.CrossRefGoogle Scholar
  58. 58.
    Kim, H.S., Kwon, H.J., Jung, I., Yun, M.R., Ahn, MJ., Kang, B.W., et al. (2015). Phase II clinical and exploratory biomarker study of dacomitinib in patients with recurrent and/or metastatic squamous cell carcinoma of head and neck. Clinical Cancer Research, 21(3):544–552.Google Scholar
  59. 59.
    Zdanov, S., Mandapathil, M., Abu Eid, R., Adamson-Fadeyi, S., Wilson, W., Qian, J., et al. (2016). Mutant KRAS conversion of conventional T cells into regulatory T cells. Cancer Immunology Research, 4(4), 354–365.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Van Allen, E. M., Lui, V. W., Egloff, A. M., Goetz, E. M., Li, H., Johnson, J. T., et al. (2015). Genomic correlate of exceptional erlotinib response in head and neck squamous cell carcinoma. JAMA Oncology, 1(2), 238–244.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Wen, Y., Li, H., Zeng, Y., Wen, W., Pendleton, K. P., Lui, V. W., et al. (2016). MAPK1E322K mutation increases head and neck squamous cell carcinoma sensitivity to erlotinib through enhanced secretion of amphiregulin. Oncotarget, 7(17), 23300–23311.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Mary Jue Xu
    • 1
  • Daniel E. Johnson
    • 1
  • Jennifer R. Grandis
    • 1
    • 2
  1. 1.Department of OtolaryngologyUniversity of California San FranciscoSan FranciscoUSA
  2. 2.Clinical and Translational Science InstituteSan FranciscoUSA

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