Recentiy 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 ofthe 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 behfl/een 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 dose 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 ofthe 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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA154303-03
Application #
8660043
Study Section
Special Emphasis Panel (ZCA1-GRB-P)
Project Start
Project End
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
3
Fiscal Year
2014
Total Cost
$268,933
Indirect Cost
$100,613
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Gannon, Hugh S; Kaplan, Nathan; Tsherniak, Aviad et al. (2016) Identification of an ""Exceptional Responder"" Cell Line to MEK1 Inhibition: Clinical Implications for MEK-Targeted Therapy. Mol Cancer Res 14:207-15
Jia, Yong; Yun, Cai-Hong; Park, Eunyoung et al. (2016) Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors. Nature 534:129-32
Kim, Eejung; Ilic, Nina; Shrestha, Yashaswi et al. (2016) Systematic Functional Interrogation of Rare Cancer Variants Identifies Oncogenic Alleles. Cancer Discov 6:714-26
Aguirre, Andrew J; Meyers, Robin M; Weir, Barbara A et al. (2016) Genomic Copy Number Dictates a Gene-Independent Cell Response to CRISPR/Cas9 Targeting. Cancer Discov 6:914-29
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
Wu, Hong; Wang, Aoli; Zhang, Wei et al. (2015) Ibrutinib selectively and irreversibly targets EGFR (L858R, Del19) mutant but is moderately resistant to EGFR (T790M) mutant NSCLC Cells. Oncotarget 6:31313-22
Lim, Sang Min; Xie, Ting; Westover, Kenneth D et al. (2015) Development of small molecules targeting the pseudokinase Her3. Bioorg Med Chem Lett 25:3382-9
Tricker, Erin M; Xu, Chunxiao; Uddin, Sharmeen et al. (2015) Combined EGFR/MEK Inhibition Prevents the Emergence of Resistance in EGFR-Mutant Lung Cancer. Cancer Discov 5:960-71
Shen, R R; Zhou, A Y; Kim, E et al. (2015) TRAF2 is an NF-*B-activating oncogene in epithelial cancers. Oncogene 34:209-16

Showing the most recent 10 out of 66 publications