The epidermal growth factor receptor (EGFR) tyrosine kinase is one of the most commonly activated oncoproteins in lung adenocarcinoma, glioblastoma and other cancers. The identification of cancer-associated EGFR mutants and their predictive power to select patients for treatment with EGFR inhibitors constitutes a major advance in treatment of these cancers. The collaborative efforts of the Eck and Meyerson laboratories over the past 12 years have provided a detailed structural and mechanistic understanding of selected activating and resistance mutations in EGFR, and have led to new classes of inhibitors that can overcome treatment-acquired resistance. In this renewal, we propose to perform studies that will inform the discovery of inhibitors of EGFR variants for which current treatments are ineffective, including exon20 insertion mutants in non-small cell lung cancer and EGFRvIII mutants in glioblastoma. In addition, we propose to probe the structure and regulation of the intact receptor to better understand its oncogenic activation. We will undertake the following Specific Aims:
Aim 1) Analyze the biochemical and structural impact of small-molecule kinase inhibitors on EGFR exon20 insertion mutants, Aim 2) Develop allosteric inhibitors that selectively inhibit the EGFRvIII variant in glioblastoma, and Aim 3) Structure elucidation of the complete EGF receptor. Execution of these aims will lead to small molecules that will serve as templates for next-generation therapeutics for EGFR- driven cancers that do not respond to current EGFR targeted agents. Additionally, our structural and biochemical studies will illuminate mechanisms of receptor activation and signaling in both normal and oncogenic contexts that may suggest new avenues for therapeutic intervention in the future.

Public Health Relevance

We are working to understand the detailed atomic structure and mechanism of regulation of the epidermal growth factor receptor and how cancer-causing mutations affect it. We use this information to develop small- molecules that specifically inhibit mutated versions of the receptor. In the long term, our work should lead to new drugs for lung cancers and glioblastomas that do not respond to current targeted therapies.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
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Forry, Suzanne L
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Dana-Farber Cancer Institute
Independent Hospitals
United States
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Jang, Jaebong; Son, Jieun; Park, Eunyoung et al. (2018) Discovery of a Highly Potent and Broadly Effective Epidermal Growth Factor Receptor and HER2 Exon 20 Insertion Mutant Inhibitor. Angew Chem Int Ed Engl 57:11629-11633
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

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