Treatment with the kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva) has shown promising results for patients with lung cancer, the leading cause of cancer death in the United States. Activating mutations in the epidermal growth factor receptor tyrosine kinase gene, EGFR, occur frequently in lung adenocarcinoma and are associated with response to these kinase inhibitors. During the past year, we and others have identified several new classes of EGFR mutation in human tumors, as described in the """"""""Preliminary Data"""""""" section. 1) A secondary kinase domain mutation, T790M, confers resistance to gefitinib and erlotinib in the setting of an activating, inhibitor-sensitive EGFR mutation. 2) One class of lung-cancer derived activating EGFR mutations, insertions within exon 20, are resistant to erlotinib and gefitinib. 3) Somatic mutations of the EGFR extracellular domain are found in glioblastoma. I now propose to conduct further studies to explore the mechanism of EGFR-dependent transformation and the mechanisms for resistance to EGFR inhibitors for tumor-derived EGFR mutations. The long-term goal of this work is to improve treatment of lung adenocarcinoma, glioblastoma, and other EGFR-dependent tumors. Specifically, I propose the following aims, tied to the recently discovered classes of EGFR mutants.
Specific Aim 1. Test the inhibition of EGFR-dependent cell growth by specific small molecule EGFR inhibitors for a panel of transforming EGFR mutations.
Specific Aim 2. Analyze the structural and biochemical determinants of EGFR-dependent transformation.
Specific Aim 3. Identify secondary mutations in activated EGFR that cause resistance to EGFR inhibitors such as gefitinib.
Specific Aim 4. Determine whether cancer-derived point mutations in the extracellular domain of EGFR are transforming and whether these mutants can be inhibited by small molecule kinase inhibitors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA116020-05
Application #
7755005
Study Section
Special Emphasis Panel (ZRG1-ONC-Q (01))
Program Officer
Forry, Suzanne L
Project Start
2006-03-24
Project End
2012-01-31
Budget Start
2010-02-01
Budget End
2012-01-31
Support Year
5
Fiscal Year
2010
Total Cost
$338,027
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Kosaka, Takayuki; Tanizaki, Junko; Paranal, Raymond M et al. (2017) Response Heterogeneity of EGFR and HER2 Exon 20 Insertions to Covalent EGFR and HER2 Inhibitors. Cancer Res 77:2712-2721
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
Fischer, Eric S; Park, Eunyoung; Eck, Michael J et al. (2016) SPLINTS: small-molecule protein ligand interface stabilizers. Curr Opin Struct Biol 37:115-22
Begley, Michael J; Yun, Cai-hong; Gewinner, Christina A et al. (2015) EGF-receptor specificity for phosphotyrosine-primed substrates provides signal integration with Src. Nat Struct Mol Biol 22:983-90
Park, Eunyoung; Kim, Nayoung; Ficarro, Scott B et al. (2015) Structure and mechanism of activity-based inhibition of the EGF receptor by Mig6. Nat Struct Mol Biol 22:703-711
Francis, Joshua M; Zhang, Cheng-Zhong; Maire, Cecile L et al. (2014) EGFR variant heterogeneity in glioblastoma resolved through single-nucleus sequencing. Cancer Discov 4:956-71
Cho, Jeonghee; Bass, Adam J; Lawrence, Michael S et al. (2014) Colon cancer-derived oncogenic EGFR G724S mutant identified by whole genome sequence analysis is dependent on asymmetric dimerization and sensitive to cetuximab. Mol Cancer 13:141
Sharifnia, Tanaz; Rusu, Victor; Piccioni, Federica et al. (2014) Genetic modifiers of EGFR dependence in non-small cell lung cancer. Proc Natl Acad Sci U S A 111:18661-6
Yasuda, Hiroyuki; Park, Eunyoung; Yun, Cai-Hong et al. (2013) Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer. Sci Transl Med 5:216ra177
Akbay, Esra A; Koyama, Shohei; Carretero, Julian et al. (2013) Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. Cancer Discov 3:1355-63

Showing the most recent 10 out of 27 publications