Lung cancer is the most common cause of cancer-related mortality in the world. Recent findings suggest that lung cancers can be subdivided according to mutations in specific proto-oncogenes. One subset of human lung adenocarcinomas is dependent on mutant epidermal growth factor receptor (EGFR) genes and responsive to drugs that inhibit protein-tyrosine kinases. The overall goals of this proposal are to use genetically engineered mice and cell lines derived from human lung cancers to enlarge our understanding of this subset of lung adenocarcinomas and to acquire new knowledge that might improve strategies for treating patients with this type of lung cancer. In pursuit of these goals, we will: (i) characterize the oncogenic properties of genetically designed mice carrying tetracycline-inducible transgenes that encode the two mutant forms of EGFR observed most commonly in human lung adenocarcinomas;(ii) compare the responses of mutant EGFR-induced tumors that occur after reduction of EGFR levels by withdrawal of antibiotics with those that occur after inhibition of EGFR protein-tyrosine kinase (TK) activity by administration of TK inhibitors (TKIs) recently introduced into therapy of human lung cancer;and (iii) identify components of the signaling pathways involved in the tumor-maintaining properties of mutant EGFR and the presumptive analogous properties of mutant KRAS by using cultured cells from human lung adenocarcinomas. This will entail screening for chemicals and inhibitory RNAs that may interfere with those pathways followed by validation of candidate signaling components and inhibitory chemicals by either interfering with or reversing lung tumorigenesis in transgenic animals.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA120247-04
Application #
7667731
Study Section
Special Emphasis Panel (ZRG1-ONC-Q (01))
Program Officer
Salnikow, Konstantin
Project Start
2006-08-22
Project End
2010-07-31
Budget Start
2009-08-07
Budget End
2010-07-31
Support Year
4
Fiscal Year
2009
Total Cost
$493,144
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Fan, Pang-Dian; Narzisi, Giuseppe; Jayaprakash, Anitha D et al. (2018) YES1 amplification is a mechanism of acquired resistance to EGFR inhibitors identified by transposon mutagenesis and clinical genomics. Proc Natl Acad Sci U S A 115:E6030-E6038
McFadden, David G; Politi, Katerina; Bhutkar, Arjun et al. (2016) Mutational landscape of EGFR-, MYC-, and Kras-driven genetically engineered mouse models of lung adenocarcinoma. Proc Natl Acad Sci U S A 113:E6409-E6417
Pirazzoli, Valentina; Ayeni, Deborah; Meador, Catherine B et al. (2016) Afatinib plus Cetuximab Delays Resistance Compared to Single-Agent Erlotinib or Afatinib in Mouse Models of TKI-Naïve EGFR L858R-Induced Lung Adenocarcinoma. Clin Cancer Res 22:426-35
Ayeni, Deborah; Politi, Katerina; Goldberg, Sarah B (2015) Emerging Agents and New Mutations in EGFR-Mutant Lung Cancer. Clin Cancer Res 21:3818-20
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
Meador, Catherine B; Jin, Hailing; de Stanchina, Elisa et al. (2015) Optimizing the sequence of anti-EGFR-targeted therapy in EGFR-mutant lung cancer. Mol Cancer Ther 14:542-52
Politi, Katerina; Herbst, Roy S (2015) Lung cancer in the era of precision medicine. Clin Cancer Res 21:2213-20
Bantikassegn, Amlak; Song, Xiaoling; Politi, Katerina (2015) Isolation of epithelial, endothelial, and immune cells from lungs of transgenic mice with oncogene-induced lung adenocarcinomas. Am J Respir Cell Mol Biol 52:409-17
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
Politi, Katerina; Gettinger, Scott (2014) Perfect ALKemy: optimizing the use of ALK-directed therapies in lung cancer. Clin Cancer Res 20:5576-8

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