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.
|Childress, Merrida A; Himmelberg, Stephen M; Chen, Huiqin et al. (2018) ALK Fusion Partners Impact Response to ALK Inhibition: Differential Effects on Sensitivity, Cellular Phenotypes, and Biochemical Properties. Mol Cancer Res 16:1724-1736|
|Johnson, Douglas B; Childress, Merrida A; Chalmers, Zachary R et al. (2018) BRAF internal deletions and resistance to BRAF/MEK inhibitor therapy. Pigment Cell Melanoma Res 31:432-436|
|Almodovar, Karinna; Iams, Wade T; Meador, Catherine B et al. (2018) Longitudinal Cell-Free DNA Analysis in Patients with Small Cell Lung Cancer Reveals Dynamic Insights into Treatment Efficacy and Disease Relapse. J Thorac Oncol 13:112-123|
|Du, Zhenfang; Lovly, Christine M (2018) Mechanisms of receptor tyrosine kinase activation in cancer. Mol Cancer 17:58|
|Fan, Pang-Dian; Narzisi, Giuseppe; Jayaprakash, Anitha D et al. (2018) YES1 amplification is a mechanism of acquired resistance to EGFR inhibitors identified by transposon mutagenesis and clinical genomics. Proc Natl Acad Sci U S A 115:E6030-E6038|
|Ichihara, Eiki; Westover, David; Meador, Catherine B et al. (2017) SFK/FAK Signaling Attenuates Osimertinib Efficacy in Both Drug-Sensitive and Drug-Resistant Models of EGFR-Mutant Lung Cancer. Cancer Res 77:2990-3000|
|Johnson, Douglas B; Frampton, Garrett M; Rioth, Matthew J et al. (2016) Targeted Next Generation Sequencing Identifies Markers of Response to PD-1 Blockade. Cancer Immunol Res 4:959-967|
|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|
|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|
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