FOA: NOT-OD-09-058 NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications PARENT GRANT: 5 R01 CA120247-03 The adenocarcinoma subtype of non-small cell lung cancer (NSCLC) appears to be rising in incidence and now comprises approximately 40 percent of all cases of lung cancer. Somatic mutations in the epidermal growth factor receptor (EGFR) gene have been identified in a subset of lung adenocarcinomas, and these mutations are associated with sensitivity to the EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib. Although the initial clinical response is often dramatic, virtually all patients will eventually develop resistance to these drugs. To enhance our understanding of tumorigenesis and resistance to EGFR TKIs, our laboratory has established a mouse model of lung adenocarcinoma by generating mice with tetracycline- inducible mutant human EGFR transgenes expressed in lung epithelium. These mice develop lung adenocarcinomas on doxycycline that rapidly regress in response to withdrawal of doxycycline or treatment with erlotinib. We are now using this model as well as human lung adenocarcinoma cell lines that harbor EGFR mutations to identify genetic lesions that can cooperate with mutant EGFRs in tumorigenesis or confer resistance to EGFR TKIs. We will screen for these genetic alterations by inducing Sleeping Beauty (SB) transposon-tagged insertional mutagenesis in vivo in mouse lung and in vitro in cell lines. Through characterization of the mutations isolated in these screens we seek to identify novel genetic lesions that contribute to the pathogenesis or response to treatment of human mutant EGFR-driven lung adenocarcinomas.

Public Health Relevance

We propose to broaden our studies of mouse models of human lung cancer to include work with a transposable element, called Sleeping Beauty (SB), that will permit us to look for mutations that accelerate EGFR-initiated tumorigenesis or promote resistance to drug therapy, issues that are directly relevant to the treatment of human lung cancers. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA120247-04S1
Application #
7847734
Study Section
Special Emphasis Panel (ZRG1-OBT-A (96))
Program Officer
Salnikow, Konstantin
Project Start
2009-09-30
Project End
2010-07-31
Budget Start
2009-09-30
Budget End
2010-07-31
Support Year
4
Fiscal Year
2009
Total Cost
$394,966
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
Lockwood, William; Politi, Katerina (2014) MYCxing it up with FGFR1 in squamous cell lung cancer. Cancer Discov 4:152-4
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

Showing the most recent 10 out of 21 publications