Acquired resistance remains a significant obstacle to optimal therapeutic outcomes for patients with lung cancer. The long-term goals of project 3 are to elucidate mechanisms of acquired resistance to targeted therapies in lung cancer and to develop rational strategies to forestall/overcome resistance. During the past 5 years, we have successfully identified mechanisms of acquired resistance to first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) and developed therapeutic strategies to overcome resistance mediated by the EGFR T790M `second-site' mutation. We participated in the characterization of the mutant-selective third-generation EGFR TKI, osimertinib, which was recently approved by the US FDA for treatment of patients with metastatic T790M-positive EGFR-mutant lung cancer after progression on EGFR TKI therapy. Unfortunately, acquired resistance to osimertinib has already emerged in patients. Here, we plan to build on our extensive experience to characterize osimertinib resistance, in both the first-line setting (i.e., in the absence of T790M) and in the second-line setting (i.e., in the presence of T790M), to parallel ongoing clinical trials. In addition, using knowledge gained from our studies of EGFR TKI resistance, we will continue to advance our studies of acquired resistance to ALK TKI therapy in ALK-rearranged lung cancer. Therapeutic targeting of ALK fusion proteins with the first-generation ALK TKI, crizotinib, has shown significant clinical activity but is limited by the development of resistant disease. Although `next generation' ALK TKIs, including ceritinib, alectinib, ensartinib, and lorlatinib can overcome resistance to crizotinib, resistance to these more potent ALK TKIs has already developed in patients. We will leverage our proven proficiency in defining resistance mechanisms combined with innovative techniques ? including forward genetic screens and siRNA screens ? as well as unique resources ? including novel cell lines and tumor biopsy samples taken at the time of disease progression on TKI therapy ? to enhance our understanding of therapeutic resistance mechanisms with the overall goal of delaying or overcoming TKI resistance in lung cancer.

Public Health Relevance

The long-term goals of project 3 are to elucidate mechanisms of acquired resistance to targeted therapies in lung cancer and to develop rational strategies to forestall/overcome resistance. In particular, we are focusing on two clinically relevant molecular subsets defined by the presence of EGFR mutations and ALK rearrangements, which combined encompass approximately 15-20% of all lung adenocarcinoma cases. 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, ALK, and other mutant tyrosine kinases.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1)
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Sloan-Kettering Institute for Cancer Research
New York
United States
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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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