Recently identified genetic alterations that drive non-small cell lung cancer provide potentially attractive targets for therapeutic intervention. In this Program, we focus on three such targets, all of which are kinases: drug-resistant mutants of the epidermal growth factor receptor (EGFR), TANK binding kinase 1 (TBKl) and discoidin domain receptor 2 (DDR2). A clear structural and mechanistic understanding of the effects of oncogenic mutations on the activity of a kinase and on inhibitor sensitivity is essential for efficient and effective development of new inhibitors. Additionally, inhibitor discovery and optimization is much more efficient when illuminated by co-crystal structures of lead compounds. The Protein Structure and Enzymology core will support each of the three projects by providing purified recombinant kinases, expertise in enzyme and inhibitor characterization, molecular modeling, and crystallographic structure determination of mutant kinases and kinase/inhibitor complexes. Centralizing these activities in the core will prevent duplication of effort and expertise in the individual projects and will leverage the resources and experience available in the Eck laboratory. We have extensive experience in the structural biology and inhibition of kinases and long-standing collaborative ties with the Project Leaders and Core Directors. Synergies between the projects (and with other projects ongoing in the Core Director's laboratory) and """"""""staged"""""""" initiation of crystallographic efforts will allow us to accomplish our aims with relatively modest resources. In close collaboration with each of the Projects and with the Chemistry Core, we will accomplish the following specific aims: 1) Crystallographic and mechanistic studies of drug-resistant mutants of the EGFR kinase 2) Expression, purification and structure determination of TBK1, and 3) Structural and mechanistic characterization of oncogenic mutants of the DDR2 tyrosine kinase.

Public Health Relevance

We are working with others in this program to use structure-guided rational drug design to create compounds that inhibit kinases EGFR, DDR2 and TBK1. These compounds will help us to understand the role of these kinase in driving non-small cell lung cancers, and may prove useful as treatments for lung or other cancers driven by these kinases.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1-GRB-P)
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Dana-Farber Cancer Institute
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Rusan, Maria; Li, Kapsok; Li, Yvonne et al. (2018) Suppression of Adaptive Responses to Targeted Cancer Therapy by Transcriptional Repression. Cancer Discov 8:59-73
Adeegbe, Dennis O; Liu, Shengwu; Hattersley, Maureen M et al. (2018) BET Bromodomain Inhibition Cooperates with PD-1 Blockade to Facilitate Antitumor Response in Kras-Mutant Non-Small Cell Lung Cancer. Cancer Immunol Res 6:1234-1245
Gannon, Hugh S; Zou, Tao; Kiessling, Michael K et al. (2018) Identification of ADAR1 adenosine deaminase dependency in a subset of cancer cells. Nat Commun 9:5450
Aguirre, Andrew J; Hahn, William C (2018) Synthetic Lethal Vulnerabilities in KRAS-Mutant Cancers. Cold Spring Harb Perspect Med 8:
Rowbotham, S P; Li, F; Dost, A F M et al. (2018) H3K9 methyltransferases and demethylases control lung tumor-propagating cells and lung cancer progression. Nat Commun 9:4559
Deng, Jiehui; Wang, Eric S; Jenkins, Russell W et al. (2018) CDK4/6 Inhibition Augments Antitumor Immunity by Enhancing T-cell Activation. Cancer Discov 8:216-233
Terai, Hideki; Kitajima, Shunsuke; Potter, Danielle S et al. (2018) ER Stress Signaling Promotes the Survival of Cancer ""Persister Cells"" Tolerant to EGFR Tyrosine Kinase Inhibitors. Cancer Res 78:1044-1057
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
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

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