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.
|Tan, Li; Gurbani, Deepak; Weisberg, Ellen L et al. (2017) Structure-guided development of covalent TAK1 inhibitors. Bioorg Med Chem 25:838-846|
|Tan, Li; Gurbani, Deepak; Weisberg, Ellen L et al. (2017) Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. Bioorg Med Chem 25:1320-1328|
|Deng, Jiehui; Wang, Eric S; Jenkins, Russell W et al. (2017) CDK4/6 Inhibition Augments Antitumor Immunity by Enhancing T-cell Activation. Cancer Discov :|
|Krall, Elsa B; Wang, Belinda; Munoz, Diana M et al. (2017) KEAP1 loss modulates sensitivity to kinase targeted therapy in lung cancer. Elife 6:|
|Adeegbe, Dennis O; Liu, Yan; Lizotte, Patrick H et al. (2017) Synergistic Immunostimulatory Effects and Therapeutic Benefit of Combined Histone Deacetylase and Bromodomain Inhibition in Non-Small Cell Lung Cancer. Cancer Discov 7:852-867|
|Majkowska, Iwona; Shitomi, Yasuyuki; Ito, Noriko et al. (2017) Discoidin domain receptor 2 mediates collagen-induced activation of membrane-type 1 matrix metalloproteinase in human fibroblasts. J Biol Chem 292:6633-6643|
|Meyers, Robin M; Bryan, Jordan G; McFarland, James M et al. (2017) Computational correction of copy number effect improves specificity of CRISPR-Cas9 essentiality screens in cancer cells. Nat Genet 49:1779-1784|
|Wang, Belinda; Krall, Elsa Beyer; Aguirre, Andrew James et al. (2017) ATXN1L, CIC, and ETS Transcription Factors Modulate Sensitivity to MAPK Pathway Inhibition. Cell Rep 18:1543-1557|
|Zhang, Haikuo; Qi, Jun; Reyes, Jaime M et al. (2016) Oncogenic Deregulation of EZH2 as an Opportunity for Targeted Therapy in Lung Cancer. Cancer Discov 6:1006-21|
|Yang, Shenghong; Imamura, Yu; Jenkins, Russell W et al. (2016) Autophagy Inhibition Dysregulates TBK1 Signaling and Promotes Pancreatic Inflammation. Cancer Immunol Res 4:520-30|
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