This Program aims to develop three protein kinases, inhibitor-resistant EGFR, TBK1, and DDR2, as therapeutic targets in non-small cell lung cancer (NSCLC). These targets were chosen because patients are treated with mutation-selective therapy but typically develop resistance (EGFR), because the mutation is common and there is no effective targeted agent but we have an excellent candidate downstream target (TBK1 for mutant KRAS), or because there is a new genomic alteration providing an opportunity for a lung cancer histology, squamous cell carcinoma, for which there is no validated target (DDR2). Our program integrates molecular and cellular pharmacology, chemistry, structural biology and mouse modeling with the overarching aim of developing specific kinase inhibitors that are active in cell-based and genetically engineered mouse models, through the following specific aims. -Overall aim 1. Develop potent and where possible mutant-selective inhibitors of inhibitor-resistant EGFR, TBK1, and DDR2 using medicinal chemistry and structure-based drug design. Core A (Chemistry) has developed promising lead compounds to inhibit pyrimidine inhibitor-resistant EGFR (Project 1), TBK1 (Project 2), and DDR2 (Project 3). Each project will collaborate with Cores A (Chemistry) and B (Structure) to optimize compounds based on cellular screens and on structural analysis of purified kinases. -Overall aim 2. Characterize kinase inhibitors and their targets pharmacologically using cellular and animal therapeutic models of lung cancer. Investigators from each Project will work with Core C (Animal) to continue generating and studying genetically engineered mouse models of lung cancer relevant to each kinase. -Overall aim 3. Employ rational design and cell-based approaches to identify inhibitor resistance mutations and to use this information in kinase inhibitor design and optimization. Our insight into resistance to EGFR inhibitors will be used to design new inhibitors that overcome drug resistance mutations for all three targets.
This Program Project will advance the development of targeted therapies for non-small cell lung cancer, the leading cause of cancer death in the United States, by validating protein kinases as targets for inhibition. This effort may also serve as a template for similar studies of other cancer types and other molecular target classes.
|Wang, J; Mikse, O; Liao, R G et al. (2015) Ligand-associated ERBB2/3 activation confers acquired resistance to FGFR inhibition in FGFR3-dependent cancer cells. Oncogene 34:2167-77|
|Berger, A H; Imielinski, M; Duke, F et al. (2014) Oncogenic RIT1 mutations in lung adenocarcinoma. Oncogene 33:4418-23|
|Nakayama, Sohei; Sng, Natasha; Carretero, Julian et al. (2014) ?-catenin contributes to lung tumor development induced by EGFR mutations. Cancer Res 74:5891-902|
|Chen, Zhao; Akbay, Esra; Mikse, Oliver et al. (2014) Co-clinical trials demonstrate superiority of crizotinib to chemotherapy in ALK-rearranged non-small cell lung cancer and predict strategies to overcome resistance. Clin Cancer Res 20:1204-11|
|Herter-Sprie, Grit S; Korideck, Houari; Christensen, Camilla L et al. (2014) Image-guided radiotherapy platform using single nodule conditional lung cancer mouse models. Nat Commun 5:5870|
|Lovly, Christine M; McDonald, Nerina T; Chen, Heidi et al. (2014) Rationale for co-targeting IGF-1R and ALK in ALK fusion-positive lung cancer. Nat Med 20:1027-34|
|Christensen, Camilla L; Kwiatkowski, Nicholas; Abraham, Brian J et al. (2014) Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor. Cancer Cell 26:909-22|
|Canning, Peter; Tan, Li; Chu, Kiki et al. (2014) Structural mechanisms determining inhibition of the collagen receptor DDR1 by selective and multi-targeted type II kinase inhibitors. J Mol Biol 426:2457-70|
|Chen, Zhao; Fillmore, Christine M; Hammerman, Peter S et al. (2014) Non-small-cell lung cancers: a heterogeneous set of diseases. Nat Rev Cancer 14:535-46|
|Akbay, Esra A; Moslehi, Javid; Christensen, Camilla L et al. (2014) D-2-hydroxyglutarate produced by mutant IDH2 causes cardiomyopathy and neurodegeneration in mice. Genes Dev 28:479-90|
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