The epidermal growth factor receptor tyrosine kinase (EGFR) 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 including erlotinib and gefitinib, has led to a major advance in cancer treatment. The collaborative efforts of the Eck and Meyerson laboratories for the past seven years have focused on understanding the structure-function relationship of cancer-derived EGFR mutants with the overarching goal of improved targeted therapies for cancers bearing these mutations. Refinement of our understanding of the mechanisms of action of mutant EGFR, and the spectrum of response of specific mutants to EGFR inhibitors, will permit more efficient development and application of EGFR-directed therapies. In this renewal, we will undertake the following Specific Aims:
Aim 1) Characterize the response of novel EGFR mutants, identified by genomic studies, to low- molecular weight ATP-competitive enzymatic inhibitors and to antibody therapies, Aim 2) Perform structural and functional studies of the exon 20 insertion mutants of EGFR, which are resistant to gefitinib, erlotinib and cetuximab, to ascertain potential therapeutic approaches, and Aim 3) Analyze the substrate specificity of wild- type and cancer-derived EGFR mutants through peptide library array experiments, mass spectrometry-based phosphoproteomics, and crystal structure determination. Execution of these aims will help define the pathogenesis of EGFR-driven tumors and will thus provide a critically important mechanistic foundation for clinical trias targeting EGFR in a variety of cancer types using known agents. Additionally, our efforts will structural and mechanistic foundation for development of next-generation EGFR inhibitors that can be effective in patients whose tumors carry EGFR mutants that are resistant to currently available inhibitors.
Mutations in the EGFR gene are a frequent cause of lung cancer, especially in non-smokers. Many different mutations have been identified, and lung cancers cause by some of these EGFR mutations respond to specific drugs such as erlotinib and gefitinib while others do not. The long term goal of our research is to understand why some EGFR mutant cancers are drug resistant, and to lay the foundations for development of drugs to target these resistant tumors.
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|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|
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|Cho, Jeonghee; Chen, Liang; Sangji, Naveen et al. (2013) Cetuximab response of lung cancer-derived EGF receptor mutants is associated with asymmetric dimerization. Cancer Res 73:6770-9|
|Cho, Jeonghee; Pastorino, Sandra; Zeng, Qing et al. (2011) Glioblastoma-derived epidermal growth factor receptor carboxyl-terminal deletion mutants are transforming and are sensitive to EGFR-directed therapies. Cancer Res 71:7587-96|
|Hammerman, Peter S; Sos, Martin L; Ramos, Alex H et al. (2011) Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer. Cancer Discov 1:78-89|
|Eck, Michael J; Yun, Cai-Hong (2010) Structural and mechanistic underpinnings of the differential drug sensitivity of EGFR mutations in non-small cell lung cancer. Biochim Biophys Acta 1804:559-66|
|Zhou, Wenjun; Ercan, Dalia; Chen, Liang et al. (2009) Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Nature 462:1070-4|
|Sos, Martin L; Koker, Mirjam; Weir, Barbara A et al. (2009) PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR. Cancer Res 69:3256-61|
|Swanson, Kenneth D; Winter, Jordan M; Reis, Marcelo et al. (2008) SOS1 mutations are rare in human malignancies: implications for Noonan Syndrome patients. Genes Chromosomes Cancer 47:253-9|
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