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Journal of Oncology
Volume 2009, Article ID 896407, 12 pages
http://dx.doi.org/10.1155/2009/896407
Review Article

Improving Response Rates to EGFR-Targeted Therapies for Head and Neck Squamous Cell Carcinoma: Candidate Predictive Biomarkers and Combination Treatment with Src Inhibitors

1Department of Otolaryngology, University of Pittsburgh, Pittsburgh, PA 15213, USA
2Department of Pharmacology, University of Pittsburgh, Pittsburgh, PA 15213, USA
3Eye and Ear Institute, Suite 500 200 Lothrop Street, Pittsburgh, PA 15213, USA

Received 14 April 2009; Accepted 17 May 2009

Academic Editor: Paul Harari

Copyright © 2009 Ann Marie Egloff and Jennifer Rubin Grandis. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. L. A. G. Ries, D. Melbert, M. Krapcho et al., SEER Cancer Statistics Review, 2007.
  2. O. Dassonville, J. L. Formento, M. Francoual et al., “Expression of epidermal growth factor receptor and survival in upper aerodigestive tract cancer,” Journal of Clinical Oncology, vol. 11, no. 10, pp. 1873–1878, 1993. View at Google Scholar
  3. J. R. Grandis, M. F. Melhem, E. L. Barnes, and D. J. Tweardy, “Quantitative immunohistochemical analysis of transforming growth factor-α and epidermal growth factor receptor in patients with squamous cell carcinoma of the head and neck,” Cancer, vol. 78, no. 6, pp. 1284–1292, 1996. View at Google Scholar
  4. K. K. Ang, N. H. Andratschke, and L. Milas, “Epidermal growth factor receptor and response of head-and-neck carcinoma to therapy,” International Journal of Radiation Oncology Biology Physics, vol. 58, no. 3, pp. 959–965, 2004. View at Publisher · View at Google Scholar
  5. J. R. Grandis, M. F. Melhem, W. E. Gooding et al., “Levels of TGF-a and EGFR protein in head and neck squamous cell carcinoma and patient survival,” Journal of the National Cancer Institute, vol. 90, no. 11, pp. 824–832, 1998. View at Google Scholar
  6. FDA approval for cetuximab, 2006.
  7. D. Soulieres, N. N. Senzer, E. E. Vokes, M. Hidalgo, S. S. Agarvala, and L. L. Siu, “Multicenter phase II study of erlotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent or metastatic squamous cell cancer of the head and neck,” Journal of Clinical Oncology, vol. 22, no. 1, pp. 77–85, 2004. View at Publisher · View at Google Scholar
  8. E. E. W. Cohen, F. Rosen, W. M. Stadler et al., “Phase II trial of ZD1839 in recurrent or metastatic squamous cell carcinoma of the head and neck,” Journal of Clinical Oncology, vol. 21, no. 10, pp. 1980–1987, 2003. View at Publisher · View at Google Scholar
  9. S. Y. Lai, P. Koppikar, S. M. Thomas et al., “Intratumoral epidermal growth factor receptor antisense DNA therapy in head and neck cancer: first human application and potential antitumor mechanisms,” Journal of Clinical Oncology, vol. 27, no. 8, pp. 1235–1242, 2009. View at Publisher · View at Google Scholar
  10. P. M. Specenier and J. B. Vermorken, “Targeted therapies in head and neck cancer,” Targeted Oncology, vol. 2, no. 2, pp. 73–88, 2007. View at Publisher · View at Google Scholar
  11. A. M. Egloff and J. Grandis, “Epidermal growth factor receptor—targeted molecular therapeutics for head and neck squamous cell carcinoma,” Expert Opinion on Therapeutic Targets, vol. 10, no. 5, pp. 639–647, 2006. View at Publisher · View at Google Scholar
  12. E. E. W. Cohen, “Role of epidermal growth factor receptor pathway-targeted therapy in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck,” Journal of Clinical Oncology, vol. 24, no. 17, pp. 2659–2665, 2006. View at Publisher · View at Google Scholar
  13. L. J. Wirth, M. R. Posner, R. B. Tishler et al., “Phase I study of pantitumumab + chemoradiotherapy (CRT) for head and neck cancer (HNC),” Journal of Clinical Oncology, vol. 26, p. 6007, 2008. View at Google Scholar
  14. K. J. Harrington, I. A. El-Hariry, C. S. Holford et al., “Phase I study of lapatinib in combination with chemoradiation in patients with locally advanced squamous cell carcinoma of the head and neck,” Journal of Clinical Oncology, vol. 27, no. 7, pp. 1100–1107, 2009. View at Publisher · View at Google Scholar
  15. J. C. Sok, F. M. Coppelli, S. M. Thomas et al., “Mutant epidermal growth factor receptor (EGFRvIII) contributes to head and neck cancer growth and resistance to EGFR targeting,” Clinical Cancer Research, vol. 12, no. 17, pp. 5064–5073, 2006. View at Publisher · View at Google Scholar
  16. J. G. Paez, P. A. Jänne, J. C. Lee et al., “EGFR mutations in lung, cancer: correlation with clinical response to gefitinib therapy,” Science, vol. 304, no. 5676, pp. 1497–1500, 2004. View at Publisher · View at Google Scholar
  17. T. J. Lynch, D. W. Bell, R. Sordella et al., “Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib,” New England Journal of Medicine, vol. 350, no. 21, pp. 2129–2139, 2004. View at Publisher · View at Google Scholar
  18. J. Loeffler-Ragg, M. Witsch-Baumgartner, A. Tzankov et al., “Low incidence of mutations in EGFR kinase domain in Caucasian patients with head and neck squamous cell carcinoma,” European Journal of Cancer, vol. 42, no. 1, pp. 109–111, 2006. View at Publisher · View at Google Scholar
  19. Y. Lemos-González, M. Páez de la Cadena, F. J. Rodríguez-Berrocal, A. M. Rodríguez-Piñeiro, E. Pallas, and D. Valverde, “Absence of activating mutations in the EGFR kinase domain in Spanish head and neck cancer patients,” Tumor Biology, vol. 28, no. 5, pp. 273–279, 2007. View at Publisher · View at Google Scholar
  20. F. R. Hirsch, R. S. Herbst, C. Olsen et al., “Increased EGFR gene copy number detected by fluorescent in situ hybridization predicts outcome in non-small-cell lung cancer patients treated with cetuximab and chemotherapy,” Journal of Clinical Oncology, vol. 26, no. 20, pp. 3351–3357, 2008. View at Publisher · View at Google Scholar
  21. M. Moroni, S. Veronese, S. Benvenuti et al., “Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study,” Lancet Oncology, vol. 6, no. 5, pp. 279–286, 2005. View at Publisher · View at Google Scholar
  22. F. Cappuzzo, G. Finocchiaro, E. Rossi et al., “EGFR FISH assay predicts for response to cetuximab in chemotherapy refractory colorectal cancer patients,” Annals of Oncology, vol. 19, no. 4, pp. 717–723, 2008. View at Publisher · View at Google Scholar
  23. A. Sartore-Bianchi, M. Moroni, S. Veronese et al., “Epidermal growth factor receptor gene copy number and clinical outcome of metastatic colorectal cancer treated with panitumumab,” Journal of Clinical Oncology, vol. 25, no. 22, pp. 3238–3245, 2007. View at Publisher · View at Google Scholar
  24. J. J.-C. Sheu, C.-H. Hua, L. Wan et al., “Functional genomic analysis identified epidermal growth factor receptor activation as the most common genetic event in oral squamous cell carcinoma,” Cancer Research, vol. 69, no. 6, pp. 2568–2576, 2009. View at Publisher · View at Google Scholar
  25. S. Ch'ng, I. Low, D. Ng et al., “Epidermal growth factor receptor: a novel biomarker for aggressive head and neck cutaneous squamous cell carcinoma,” Human Pathology, vol. 39, no. 3, pp. 344–349, 2008. View at Publisher · View at Google Scholar
  26. W.-F. Chiang, S.-Y. Liu, C.-Y. Yen et al., “Association of epidermal growth factor receptor (EGFR) gene copy number amplification with neck lymph node metastasis in areca-associated oral carcinomas,” Oral Oncology, vol. 44, no. 3, pp. 270–276, 2008. View at Publisher · View at Google Scholar
  27. S. Temam, H. Kawaguchi, A. K. El-Naggar et al., “Epidermal growth factor receptor copy number alterations correlate with poor clinical outcome in patients with head and neck squamous cancer,” Journal of Clinical Oncology, vol. 25, no. 16, pp. 2164–2170, 2007. View at Publisher · View at Google Scholar
  28. C. H. Chung, K. Ely, L. McGavran et al., “Increased epidermal growth factor receptor gene copy number is associated with poor prognosis in head and neck squamous cell carcinomas,” Journal of Clinical Oncology, vol. 24, no. 25, pp. 4170–4176, 2006. View at Publisher · View at Google Scholar
  29. M. Hanawa, S. Suzuki, Y. Dobashi et al., “EGFR protein overexpression and gene amplification in squamous cell carcinomas of the esophagus,” International Journal of Cancer, vol. 118, no. 5, pp. 1173–1180, 2006. View at Publisher · View at Google Scholar
  30. M. Mrhalova, J. Plzak, J. Betka, and R. Kodet, “Epidermal growth factor receptor—its expression and copy numbers of EGFR gene in patients with head and neck squamous cell carcinomas,” Neoplasma, vol. 52, no. 4, pp. 338–343, 2005. View at Google Scholar
  31. D. K. Koynova, V. S. Tsenova, and D. I. Toncheva, “Tissue microarray analysis of C-MYC oncogene copy number changes in larynx carcinoma,” ORL, vol. 67, no. 2, pp. 92–95, 2005. View at Publisher · View at Google Scholar
  32. K. Freier, C. Flechtenmacher, A. Walch et al., “Copy number gains on 22q13 in adenoid cystic carcinoma of the salivary gland revealed by comparative genomic hybridization and tissue microarray analysis,” Cancer Genetics and Cytogenetics, vol. 159, no. 1, pp. 89–95, 2005. View at Publisher · View at Google Scholar
  33. I. A. Lea, M. A. Jackson, X. Li, S. Bailey, S. D. Peddada, and J. K. Dunnick, “Genetic pathways and mutation profiles of human cancers: site- and exposure-specific patterns,” Carcinogenesis, vol. 28, no. 9, pp. 1851–1858, 2007. View at Publisher · View at Google Scholar
  34. S. A. Forbes, G. Bhamra, S. Bamford et al., “The catalogue of somatic mutations in cancer (COSMIC),” in Current Protocols in Human Genetics, chapter 10, unit 10 11, 2008. View at Publisher · View at Google Scholar
  35. J. A. Anderson, J. C. Irish, C. M. McLachlin, and B. Y. Ngan, “H-ras oncogene mutation and human papillomavirus infection in oral carcinomas,” Archives of Otolaryngology: Head and Neck Surgery, vol. 120, no. 7, pp. 755–760, 1994. View at Google Scholar
  36. A. K. Murugan, N. T. Hong, Y. Fukui, A. K. Munirajan, and N. Tsuchida, “Oncogenic mutations of the PIK3CA gene in head and neck squamous cell carcinomas,” International Journal of Oncology, vol. 32, no. 1, pp. 101–111, 2008. View at Google Scholar
  37. I. Fenic, K. Steger, C. Gruber, C. Arens, and J. Woenckhaus, “Analysis of PIK3CA and Akt/protein kinase B in head and neck squamous cell carcinoma.,” Oncology Reports, vol. 18, no. 1, pp. 253–259, 2007. View at Google Scholar
  38. W. Qiu, F. Schönleben, X. Li et al., “PIK3CA mutations in head and neck squamous cell carcinoma,” Clinical Cancer Research, vol. 12, no. 5, pp. 1441–1446, 2006. View at Publisher · View at Google Scholar
  39. K.-I. Kozaki, I. Imoto, A. Pimkhaokham et al., “PIK3CA mutation is an oncogenic aberration at advanced stages of oral squamous cell carcinoma,” Cancer Science, vol. 97, no. 12, pp. 1351–1358, 2006. View at Publisher · View at Google Scholar
  40. K. H. Shin, J. M. Kim, K. S. Rho, K. H. Park, J. E. Oh, and B. M. Min, “Inactivation of the PTEN gene by mutation, exonic deletion, and loss of transcript in human oral squamous cell carcinomas,” International Journal of Oncology, vol. 21, no. 5, pp. 997–1001, 2002. View at Google Scholar
  41. M. Poetsch, G. Lorenz, and B. Kleist, “Detection of new PTEN/MMAC1 mutations in head and neck squamous cell carcinomas with loss of chromosome 10,” Cancer Genetics and Cytogenetics, vol. 132, no. 1, pp. 20–24, 2002. View at Publisher · View at Google Scholar
  42. A. Mavros, M. Hahn, I. Wieland et al., “Infrequent genetic alterations of the tumor suppressor gene PTEN/MMAC1 in squamous cell carcinoma of the oral cavity,” Journal of Oral Pathology and Medicine, vol. 31, no. 5, pp. 270–276, 2002. View at Publisher · View at Google Scholar
  43. X. Shao, R. Tandon, G. Samara et al., “Mutational analysis of the PTEN gene in head and neck squamous cell carcinoma,” International Journal of Cancer, vol. 77, no. 5, pp. 684–688, 1998. View at Google Scholar
  44. S. Dacic, M. Flanagan, K. Cieply et al., “Significance of EGFR protein expression and gene amplification in non-small cell lung carcinoma,” American Journal of Clinical Pathology, vol. 125, no. 6, pp. 860–865, 2006. View at Publisher · View at Google Scholar
  45. A. Ooi, T. Takehana, X. Li et al., “Protein overexpression and gene amplification of HER-2 and EGFR in colorectal cancers: an immunohistochemical and fluorescent in situ hybridization study,” Modern Pathology, vol. 17, no. 8, pp. 895–904, 2004. View at Publisher · View at Google Scholar
  46. A. Berns, “Kras and Hras—what is the difference?” Nature Genetics, vol. 40, no. 10, pp. 1149–1150, 2008. View at Publisher · View at Google Scholar
  47. H. Linardou, I. J. Dahabreh, D. Kanaloupiti et al., “Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer,” The Lancet Oncology, vol. 9, no. 10, pp. 962–972, 2008. View at Publisher · View at Google Scholar
  48. F. Cappuzzo, M. Varella-Garcia, G. Finocchiaro et al., “Primary resistance to cetuximab therapy in EGFR FISH-positive colorectal cancer patients,” British Journal of Cancer, vol. 99, no. 1, pp. 83–89, 2008. View at Publisher · View at Google Scholar
  49. F. Le Calvez, A. Mukeria, J. D. Hunt et al., “TP53 and KRAS mutation load and types in lung cancers in relation to tobacco smoke: distinct patterns in never, former, and current smokers,” Cancer Research, vol. 65, no. 12, pp. 5076–5083, 2005. View at Publisher · View at Google Scholar
  50. H. Shigematsu, L. Lin, T. Takahashi et al., “Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers,” Journal of the National Cancer Institute, vol. 97, no. 5, pp. 339–346, 2005. View at Publisher · View at Google Scholar
  51. E. S. Schernhammer, E. Giovannuccci, C. S. Fuchs, and S. Ogino, “A prospective study of dietary folate and vitamin B and colon cancer according to microsatellite instability and KRAS mutational status,” Cancer Epidemiology Biomarkers and Prevention, vol. 17, no. 10, pp. 2895–2898, 2008. View at Publisher · View at Google Scholar
  52. M. D. To, C. E. Wong, A. N. Karnezis, R. Del Rosario, R. Di Lauro, and A. Balmain, “Kras regulatory elements and exon 4A determine mutation specificity in lung cancer,” Nature Genetics, vol. 40, no. 10, pp. 1240–1244, 2008. View at Publisher · View at Google Scholar
  53. A. Sartore-Bianchi, M. Martini, F. Molinari et al., “PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies,” Cancer Research, vol. 69, no. 5, pp. 1851–1857, 2009. View at Publisher · View at Google Scholar
  54. Q. Nie, Z. Wang, G. Zhang et al., “The epidermal growth factor receptor intron1 (CA) n microsatellite polymorphism is a potential predictor of treatment outcome in patients with advanced lung cancer treated with Gefitinib,” European Journal of Pharmacology, vol. 570, no. 1–3, pp. 175–181, 2007. View at Publisher · View at Google Scholar
  55. M. Tiseo, M. Capelletti, G. De Palma et al., “Epidermal growth factor receptor intron-1 polymorphism predicts gefitinib outcome in advanced non-small cell lung cancer,” Journal of Thoracic Oncology, vol. 3, no. 10, pp. 1104–1111, 2008. View at Google Scholar
  56. F. Graziano, A. Ruzzo, F. Loupakis et al., “Pharmacogenetic profiling for cetuximab plus irinotecan therapy in patients with refractory advanced colorectal cancer,” Journal of Clinical Oncology, vol. 26, no. 9, pp. 1427–1434, 2008. View at Publisher · View at Google Scholar
  57. V. Gregorc, M. Hidalgo, A. Spreafico et al., “Germline polymorphisms in EGFR and survival in patients with lung cancer receiving gefitinib,” Clinical Pharmacology and Therapeutics, vol. 83, no. 3, pp. 477–484, 2008. View at Publisher · View at Google Scholar
  58. F. Gebhardt, H. Bürger, and B. Brandt, “Modulation of EGFR gene transcription by a polymorphic repetitive sequence—a link between genetics and epigenetics,” International Journal of Biological Markers, vol. 15, no. 1, pp. 105–110, 2000. View at Google Scholar
  59. M.-C. Etienne-Grimaldi, S. Pereira, N. Magné et al., “Analysis of the dinucleotide repeat polymorphism in the epidermal growth factor receptor (EGFR) gene in head and neck cancer patients,” Annals of Oncology, vol. 16, no. 6, pp. 934–941, 2005. View at Publisher · View at Google Scholar
  60. W. Liu, F. Innocenti, M. H. Wu et al., “A functional common polymorphism in a Sp1 recognition site of the epidermal growth factor receptor gene promoter,” Cancer Research, vol. 65, no. 1, pp. 46–53, 2005. View at Google Scholar
  61. M. Nomura, H. Shigematsu, L. Li et al., “Polymorphisms, mutations, and amplification of the EGFR gene in non-small cell lung cancers,” PLoS Medicine, vol. 4, no. 4, article e125, 2007. View at Publisher · View at Google Scholar
  62. A. Gonçalves, S. Esteyries, B. Taylor-Smedra et al., “A polymorphism of EGFR extracellular domain is associated with progression free-survival in metastatic colorectal cancer patients receiving cetuximab-based treatment,” BMC Cancer, vol. 8, article 169, 2008. View at Publisher · View at Google Scholar
  63. F. Bibeau, E. Lopez-Crapez, F. Di Fiore et al., “Impact of Fc?RIIa-Fc?RIIIa polymorphisms and KRAS mutations on the clinical outcome of patients with metastatic colorectal cancer treated with cetuximab plus irinotecan,” Journal of Clinical Oncology, vol. 27, no. 7, pp. 1122–1129, 2009. View at Publisher · View at Google Scholar
  64. A. López-Albaitero, S. C. Lee, S. Morgan et al., “Role of polymorphic Fc gamma receptor IIIa and EGFR expression level in cetuximab mediated, NK cell dependent in vitro cytotoxicity of head and neck squamous cell carcinoma cells,” Cancer Immunology, Immunotherapy. In press. View at Publisher · View at Google Scholar
  65. R. J. Taylor, S.-L. Chan, A. Wood et al., “Fc?RIIIa polymorphisms and cetuximab induced cytotoxicity in squamous cell carcinoma of the head and neck,” Cancer Immunology, Immunotherapy, vol. 58, no. 7, pp. 997–1006, 2009. View at Publisher · View at Google Scholar
  66. C. A. Lowell and P. Soriano, “Knockouts of Src-family kinases: stiff bones, wimpy T cells, and bad memories,” Genes and Development, vol. 10, no. 15, pp. 1845–1857, 1996. View at Google Scholar
  67. S. M. Thomas and J. S. Brugge, “Cellular functions regulated by SRC family kinases,” Annual Review of Cell and Developmental Biology, vol. 13, pp. 513–609, 1997. View at Publisher · View at Google Scholar
  68. J. M. Summy and G. E. Gallick, “Src family kinases in tumor progression and metastasis,” Cancer and Metastasis Reviews, vol. 22, no. 4, pp. 337–358, 2003. View at Publisher · View at Google Scholar
  69. S. Xi, Q. Zhang, K. F. Dyer et al., “Src kinases mediate STAT growth pathways in squamous cell carcinoma of the head and neck,” Journal of Biological Chemistry, vol. 278, no. 34, pp. 31574–31583, 2003. View at Publisher · View at Google Scholar
  70. Z. Yang, R. Bagheri-Yarmand, R.-A. Wang et al., “The epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 (Iressa) suppresses c-Src and Pak1 pathways and invasiveness of human cancer cells,” Clinical Cancer Research, vol. 10, no. 2, pp. 658–667, 2004. View at Publisher · View at Google Scholar
  71. Q. Zhang, S. M. Thomas, V. W. Y. Lui et al., “Phosphorylation of TNF-a converting enzyme by gastrin-releasing peptide induces amphiregulin release and EGF receptor activation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 18, pp. 6901–6906, 2006. View at Publisher · View at Google Scholar
  72. Q. Zhang, S. M. Thomas, S. Xi et al., “Src family kinases mediate epidermal growth factor receptor ligand cleavage, proliferation, and invasion of head and neck cancer cells,” Cancer Research, vol. 64, no. 17, pp. 6166–6173, 2004. View at Publisher · View at Google Scholar
  73. X. Li, Y. Yang, Y. Hu et al., “avß6-Fyn signaling promotes oral cancer progression,” Journal of Biological Chemistry, vol. 278, no. 43, pp. 41646–41653, 2003. View at Publisher · View at Google Scholar
  74. R. B. Irby and T. J. Yeatman, “Role of Src expression and activation in human cancer,” Oncogene, vol. 19, no. 49, pp. 5636–5642, 2000. View at Google Scholar
  75. Y. Daigo, Y. Furukawa, T. Kawasoe et al., “Absence of genetic alteration at codon 531 of the human c-src gene in 479 advanced colorectal cancers from Japanese and Caucasian patients,” Cancer Research, vol. 59, no. 17, pp. 4222–4224, 1999. View at Google Scholar
  76. M. Nilbert and E. Fernebro, “Lack of activating c-SRC mutations at codon 531 in rectal cancer,” Cancer Genetics and Cytogenetics, vol. 121, no. 1, pp. 94–95, 2000. View at Publisher · View at Google Scholar
  77. N. Gavert and A. Ben-Ze'ev, “Epithelial-mesenchymal transition and the invasive potential of tumors,” Trends in Molecular Medicine, vol. 14, no. 5, pp. 199–209, 2008. View at Publisher · View at Google Scholar
  78. P. Savagner, “Leaving the neighborhood: molecular mechanisms involved during epithelial-mesenchymal transition,” BioEssays, vol. 23, no. 10, pp. 912–923, 2001. View at Publisher · View at Google Scholar
  79. M. Mandal, J. N. Myers, S. M. Lippman et al., “Epithelial to mesenchymal transition in head and neck squamous carcinoma: association of Src activation with E-cadherin down-regulation, vimentin expression, and aggressive tumor features,” Cancer, vol. 112, no. 9, pp. 2088–2100, 2008. View at Publisher · View at Google Scholar
  80. F. M. Johnson, B. Saigal, M. Talpaz, and N. J. Donato, “Dasatinib (BMS-354825) tyrosine kinase inhibitor suppresses invasion and induces cell cycle arrest and apoptosis of head and neck squamous cell carcinoma and non-small cell lung cancer cells,” Clinical Cancer Research, vol. 11, no. 19, pp. 6924–6932, 2005. View at Publisher · View at Google Scholar
  81. S. Barr, S. Thomson, E. Buck et al., “Bypassing cellular EGF receptor dependence through epithelial-to- mesenchymal-like transitions,” Clinical and Experimental Metastasis, vol. 25, no. 6, pp. 685–693, 2008. View at Publisher · View at Google Scholar
  82. J. Cooper, M. M. Mita, J. Curtright et al., “A phase I study examining weekly dosing and pharmacokinetics (PK) of a novel spectrum selective kinase inhibitor, XL999, in patients (pts) with advanced solid malignancies (ASM),” Journal of Clinical Oncology, vol. 24, no. 18, supplement, 2006, abstract no. 13024. View at Google Scholar
  83. L. Cripe, W. McGuire, M. Wertheim et al., “Integrated report of the phase 2 experience with XL999 administered IV to patients (pts) with NSCLC, renal cell CA (RCC), metastatic colorectal CA (CRC), recurrent ovarian CA, accute myelogenous leaukemia (AML), and multiple myeloma (MM),” Journal of Clinical Oncology, vol. 25, no. 18, supplement, 2007, abstract no. 3591. View at Google Scholar
  84. R. J. March, B. Mirtsching, S. Modi et al., “A phase II study of XL999 in patients (pts) with NSCLC,” Journal of Clinical Oncology, vol. 25, no. 18, supplement, 2007, abstract no. 18112. View at Google Scholar
  85. D. Hangauer, I. Gelman, L. Dyster et al., “Potent and selective in vitro and in vivo inhibition of tumor proliferation by KX01, a novel non-ATP competitive Src inhibitor,” in Proceedings of the AACR Meeting, 2007, abstracts no. 3245.
  86. L. J. Lombardo, F. Y. Lee, P. Chen et al., “Discovery of N-(2-chloro-6-methylphenyl)-2-(6-(4-(2-hydroxyethyl)- piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays,” Journal of Medicinal Chemistry, vol. 47, no. 27, pp. 6658–6661, 2004. View at Publisher · View at Google Scholar
  87. L. F. Hennequin, J. Allen, J. Breed et al., “N-(5-chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy] -5-(tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine, a novel, highly selective, orally available, dual-specific c-Src/Abl kinase inhibitor,” Journal of Medicinal Chemistry, vol. 49, no. 22, pp. 6465–6488, 2006. View at Publisher · View at Google Scholar
  88. P. Koppikar, S.-H. Choi, A. M. Egloff et al., “Combined inhibition of c-Src and epidermal growth factor receptor abrogates growth and invasion of head and neck squamous cell carcinoma,” Clinical Cancer Research, vol. 14, no. 13, pp. 4284–4291, 2008. View at Publisher · View at Google Scholar
  89. D. L. Wheeler, M. Iida, T. J. Kruser et al., “Epidermal growth factor receptor cooperates with Src family kinases in acquired resistance to cetuximab,” Cancer Biology and Therapy, vol. 8, no. 8, pp. 696–703, 2009. View at Google Scholar
  90. T. M. Fieinstein, S. Agrawal, R. G. Stoller et al., “Phase I and pharmacokinetic (PK) study of dasatinib (D) and cetuximab (C) in patients (pts) with advanced solid malignancies,” in Proceedings of the ASCO, 2009.
  91. A. A. Adjei, M. Christian, and P. Ivy, “Novel designs and end points for phase II clinical trials,” Clinical Cancer Research, vol. 15, no. 6, pp. 1866–1872, 2009. View at Publisher · View at Google Scholar