. This proposal describes a training program for the development of the candidate's academic career in cancer biology. Throughout the period of this award, the candidate will develop her independent research program. She will also use this time to build on her scientific knowledge and mentoring skills. The candidate will be mentored by Dr. Harold Varmus, a leader in the field of cancer biology who has trained numerous successful scientists. Memorial Sloan-Kettering Cancer Center (MSKCC) will provide institutional support, including ample resources, career development activities and opportunities for interactions between scientists and clinicians to help the candidate achieve her goals. The research focuses on lung cancer, the most common cancer worldwide. The candidate has recently generated two mouse models of lung cancer based on expression of mutant Epidermal Growth Factor Receptors (EGFRs) in lung epithelial cells. She has established that the lung cancer-associated EGFR mutants can initiate lung tumorigenesis and are required for tumor maintenance. The goals of this research proposal are to determine how the phenotype and clinical behavior of EGFR mutant lung tumors are influenced by: 1) the levels of expression of EGFR; 2) the presence of other EGFR family members; and, 3) cooperating genetic lesions.
The specific aims are to use these new mouse models to: 1) Elucidate the mechanisms of mutant EGFR-induced transformation of lung epithelial cells; and, 2) Identify genes that cooperate with mutant EGFR in lung tumorigenesis. Findings in the mouse models will be verified in human lung cancer specimens. Relevance. EGFR mutations are found in approximately 10% of non-small cell lung cancer cases in the US and are associated with sensitivity to the tyrosine kinase inhibitors, gefitinib and erlotinib. This proposal addresses questions directly relevant to this subset of lung cancers: 1) How do the EGFR mutants transform lung cells? 2) Why do some patients who have tumors with EGFR mutations NOT respond to tyrosine kinase inhibitor treatment? 3) What are the causes of acquired resistance to tyrosine kinase inhibitor treatment?

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Transition Award (R00)
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Study Section
Special Emphasis Panel (NSS)
Program Officer
Salnikow, Konstantin
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Yale University
Schools of Medicine
New Haven
United States
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Song, Xiaoling; Fan, Pang-Dian; Bantikassegn, Amlak et al. (2015) ERBB3-independent activation of the PI3K pathway in EGFR-mutant lung adenocarcinomas. Cancer Res 75:1035-45
Pirazzoli, Valentina; Politi, Katerina (2014) Generation of drug-resistant tumors using intermittent dosing of tyrosine kinase inhibitors in mouse. Cold Spring Harb Protoc 2014:178-81
Pirazzoli, Valentina; Nebhan, Caroline; Song, Xiaoling et al. (2014) Acquired resistance of EGFR-mutant lung adenocarcinomas to afatinib plus cetuximab is associated with activation of mTORC1. Cell Rep 7:999-1008
de Bruin, Elza C; Cowell, Catherine; Warne, Patricia H et al. (2014) Reduced NF1 expression confers resistance to EGFR inhibition in lung cancer. Cancer Discov 4:606-19
Berger, Alice H; Chen, Ming; Morotti, Alessandro et al. (2013) DOK2 inhibits EGFR-mutated lung adenocarcinoma. PLoS One 8:e79526
Lee, Ho-June; Schaefer, Gabriele; Heffron, Timothy P et al. (2013) Noncovalent wild-type-sparing inhibitors of EGFR T790M. Cancer Discov 3:168-81
Jia, Peilin; Jin, Hailing; Meador, Catherine B et al. (2013) Next-generation sequencing of paired tyrosine kinase inhibitor-sensitive and -resistant EGFR mutant lung cancer cell lines identifies spectrum of DNA changes associated with drug resistance. Genome Res 23:1434-45
Takezawa, Ken; Pirazzoli, Valentina; Arcila, Maria E et al. (2012) HER2 amplification: a potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFRT790M mutation. Cancer Discov 2:922-33
Politi, Katerina; Lynch, Thomas J (2012) Two sides of the same coin: EGFR exon 19 deletions and insertions in lung cancer. Clin Cancer Res 18:1490-2
Politi, Katerina; Pao, William (2011) How genetically engineered mouse tumor models provide insights into human cancers. J Clin Oncol 29:2273-81