EGFR mutant lung cancer is a subset of lung cancer with unique biological and clinical features. Over 70% of patients whose lung cancers harbor specific mutations within the exons encoding the tyrosine kinase domain of EGFR experience radiographic responses to the selective EGFR tyrosine kinase inhibitors (TKIs), gefitinib (Iressa) or eriotinib (Tarceva), and overall median survival is about 30 months. However, no patients are cured. After about one year, acquired resistance develops. In previous work, we showed that in addition to primary drug-sensitive EGFR mutations, tumor cells from more than half of patients with such """"""""acquired resistance"""""""" contain a recurrent second-site mutation (T790M) in the EGFR kinase domain. We also demonstrated using mouse models of lung cancer that T790M-mediated resistance could be overcome by a novel combination ofthe second-generation EGFR TKI, afatinib (BIBW2992), and the anti-EGFR antibody, cetuximab. A Phase IB clinical trial ofthis combination in humans, based upon our data, has now shown unprecedented activity in this patient cohort, with a 95% clinical benefit rate and a 35% confirmed radiographic response rate. The clinical findings have stimulated new and critical biological questions to address. Here, based upon promising new preliminary data, we aim to 1) elucidate the role of HER2 in mediating sensitivity of T790M-harboring EGFR mutant lung cancer cells to afatinib/cetuximab, and 2) identify in EGFR mutant kinases intrinsic regulatory domains required for full kinase function. An improved understanding of mechanisms and modulators of sensitivity and resistance to EGFR inhibitors 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.

Public Health Relevance

Lung cancers are America's leading cancer killers, responsible for 158,000 deaths this year. This grant addresses the two most critical roadblocks to improving the care and curability of persons with these illnesses: (1) understanding how cancers spread (metastasis) and (2) the lack of highly effective medicines to prevent spread or to eradicate cancers that have spread from the lung.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Sloan-Kettering Institute for Cancer Research
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Mo, Qianxing; Shen, Ronglai; Guo, Cui et al. (2018) A fully Bayesian latent variable model for integrative clustering analysis of multi-type omics data. Biostatistics 19:71-86
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
Gao, Yijun; Chang, Matthew T; McKay, Daniel et al. (2018) Allele-Specific Mechanisms of Activation of MEK1 Mutants Determine Their Properties. Cancer Discov 8:648-661
Arbour, Kathryn C; Jordan, Emmett; Kim, Hyunjae Ryan et al. (2018) Effects of Co-occurring Genomic Alterations on Outcomes in Patients with KRAS-Mutant Non-Small Cell Lung Cancer. Clin Cancer Res 24:334-340
Gallant, Jean-Nicolas; Lovly, Christine M (2018) Established, emerging and elusive molecular targets in the treatment of lung cancer. J Pathol 244:565-577
Hellmann, Matthew D; Nathanson, Tavi; Rizvi, Hira et al. (2018) Genomic Features of Response to Combination Immunotherapy in Patients with Advanced Non-Small-Cell Lung Cancer. Cancer Cell 33:843-852.e4
Yao, Zhan; Gao, Yijun; Su, Wenjing et al. (2018) RAF inhibitor PLX8394 selectively disrupts BRAF dimers and RAS-independent BRAF-mutant-driven signaling. Nat Med :
Suzawa, Ken; Offin, Michael; Lu, Daniel et al. (2018) Activation of KRAS Mediates Resistance to Targeted Therapy in MET Exon 14-mutant Non-small Cell Lung Cancer. Clin Cancer Res :
Yu, Helena A; Planchard, David; Lovly, Christine M (2018) Sequencing Therapy for Genetically Defined Subgroups of Non-Small Cell Lung Cancer. Am Soc Clin Oncol Educ Book :726-739
Yuan, Tina L; Amzallag, Arnaud; Bagni, Rachel et al. (2018) Differential Effector Engagement by Oncogenic KRAS. Cell Rep 22:1889-1902

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