Over 70% of patients whose lung cancers harbor specific mutations within the exons encoding the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) experience radiographic responses to the selective EGFR tyrosine kinase inhibitors (TKIs), gefitinib (Iressa) or erlotinib (Tarceva). However, after about one year, these patients develop progression of disease. No targeted therapy has proven clinically effective in treating acquired resistance. In the previously funded period, we identified several mechanisms of acquired resistance, including second-site EGFR mutations (>50% of cases) and amplification of the gene encoding the MET tyrosine kinase (up to 20% of cases). Using mouse models of lung cancer that we generated and characterized, we also showed that the most common form of resistance, mediated by the EGFR T790M mutation, could be overcome by a novel combination of the second-generation EGFR TKI, afatinib (BIBW2992), and the anti-EGFR antibody, cetuximab. A Phase IB/II clinical trial of this combination in humans has now shown unprecedented activity in this patient cohort with a 36% (8 of 22) radiographic response rate. However, at least one patient on this combination has already developed progressive disease, and surprisingly, some tumors without T790M have also responded. The overall goals of this revised proposal are to use human tumor specimens and cell lines, genetically engineered and xenograft mouse models, and various molecular and biochemical techniques to gain further knowledge about the subset of EGFR mutant harboring lung cancers that develop acquired resistance to EGFR inhibition. An improved understanding of acquired resistance will hopefully allow us to treat/suppress the development of progressive disease and provide new insights into the biology of cancers driven by EGFR or other mutant receptor tyrosine kinases.
A new clinical trial involving two targeted agents (afatinib plus cetuximab) was rationally designed based upon findings from our previous funding period and has now shown unprecedented anti-tumor activity in patients with acquired resistance to EGFR tyrosine kinase inhibitors in lung cancer. The goal of this grant is to gain further knowledge about the subset of EGFR mutant harboring lung cancers that develop acquired resistance to EGFR inhibition. An improved understanding of acquired resistance will hopefully allow us to treat/suppress the development of progressive disease and provide new insights into the biology of cancers driven by EGFR or other mutant receptor tyrosine kinases.
|Pirazzoli, Valentina; Ayeni, Deborah; Meador, Catherine B et al. (2016) Afatinib plus Cetuximab Delays Resistance Compared to Single-Agent Erlotinib or Afatinib in Mouse Models of TKI-NaÃ¯ve EGFR L858R-Induced Lung Adenocarcinoma. Clin Cancer Res 22:426-35|
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|Amato, Katherine R; Wang, Shan; Tan, Li et al. (2016) EPHA2 Blockade Overcomes Acquired Resistance to EGFR Kinase Inhibitors in Lung Cancer. Cancer Res 76:305-18|
|Konduri, Kartik; Gallant, Jean-Nicolas; Chae, Young Kwang et al. (2016) EGFR Fusions as Novel Therapeutic Targets in Lung Cancer. Cancer Discov 6:601-11|
|McFadden, David G; Politi, Katerina; Bhutkar, Arjun et al. (2016) Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma. Proc Natl Acad Sci U S A 113:E6409-E6417|
|Dragani, Tommaso A; Castells, Antoni; Kulasingam, Vathany et al. (2016) Major milestones in translational oncology. BMC Med 14:110|
|Machiela, Mitchell J; Zhou, Weiyin; Karlins, Eric et al. (2016) Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome. Nat Commun 7:11843|
|Johnson, Douglas B; Estrada, Monica V; Salgado, Roberto et al. (2016) Melanoma-specific MHC-II expression represents a tumour-autonomous phenotype and predicts response to anti-PD-1/PD-L1 therapy. Nat Commun 7:10582|
|Qiao, Huan; Lovly, Christine M (2016) Cracking the Code of Resistance across Multiple Lines of ALK Inhibitor Therapy in Lung Cancer. Cancer Discov 6:1084-1086|
|Lovly, Christine M (2015) Combating acquired resistance to tyrosine kinase inhibitors in lung cancer. Am Soc Clin Oncol Educ Book :e165-73|
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