. During the first three years of this award, we have characterized mouse models of lung adenocarcinoma initiated by doxycycline-inducible transgenes encoding the two common forms of mutant EGFR found in the corresponding type of human cancer. These mice develop tumors indistinguishable from the human cancers;the tumors regress when the oncogene is de-induced or when the mutant kinase is inhibited with drugs used in patients, and they develop drug resistance under certain conditions, in some cases as a result of a secondary mutation in EGFR also found in about half of drug-resistant tumors in patients. We now propose to extend our work with these mouse models in several ways with the goals of (i) evaluating genes and proteins (including tumor suppressor genes, members of the EGFR family, and phosphotyrosine-containing proteins) that might influence EGFR-initiated lung tumorigenesis;(ii) discovering additional genes that contribute to tumor formation, progression or drug resistance;(iii) assessing the potential of tumors with various genotypes to metastasize and become established cell lines in culture;and (iv) studying the origins and functions of inflammatory cells observed in these mouse tumors. To pursue these goals, we will take advantage of several conditional mouse mutants, results from our own proteomics surveys, the Sleeping Beauty transposition system, and methods for characterization of immune cells. We expect our findings to offer new insights into EGFR-mediated lung carcinogenesis, tumor progression, secondary drug resistance, and the role of immune cells in solid tumors. In addition, we may generate new mouse tumor cell lines for experimental use and identify genes that are useful for diagnosis, classification, and treatment of lung cancers.

Public Health Relevance

Lung cancer is the major cause of death from cancer in the United States and the world, and adenocarcinoma is the most common form of lung cancer. Our laboratory is among those who found that about ten percent of patients in the US with lung adenocarcinomas respond to a new set of drugs--- drugs that inhibit a type of enzyme called a protein-tyrosine kinase---because their cancers are caused by one of two characteristic mutations affecting a growth factor receptor called EGFR. Unfortunately, the beneficial response to these drugs is short-lived;in about half the cases, the acquired drug resistance is due to a second mutation in the EGFR gene that we discovered a few years ago. To study this type of lung cancer more thoroughly than is possible in human patients, we have manipulated genes in mice so that the animals develop lung cancers that are very similar to human lung cancers with EGFR mutations; as we have shown during the first phase of this grant, the cancers respond to the same drugs, develop similar drug resistance, and disappear if the mutant gene is turned off. We now propose to use these powerful models to study a number of related aspects of lung cancer. First, we will look at the roles that might be played by other genes when mutant EGFR causes lung cancer. These other genes include well-known tumor suppressor genes and genes identified through studies we have done to characterize proteins that are modified by EGFR or related enzymes in lung cancer cells. In the course of this work, we will also ask what is required to make lung cancer cells metastasize to other sites and attempt to develop mouse lung cancer cell lines from the metastases. To seek novel genes that might contribute to accelerated growth of a lung cancer or to the development of drug resistance, we will make use of a moveable DNA unit that can identify such genes. Finally, we will explore the striking appearance of immune cells in mouse lung tumors, in an effort to understand how such cells arrived in the lung tissue and what functions they serve to promote or retard tumor development.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01CA120247-09
Application #
8677742
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Salnikow, Konstantin
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Yale University
Department
Pathology
Type
Schools of Medicine
DUNS #
City
New Haven
State
CT
Country
United States
Zip Code
06510
Politi, Katerina; Gettinger, Scott (2014) Perfect ALKemy: optimizing the use of ALK-directed therapies in lung cancer. Clin Cancer Res 20:5576-8
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
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
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
Lee, Ho-June; Schaefer, Gabriele; Heffron, Timothy P et al. (2013) Noncovalent wild-type-sparing inhibitors of EGFR T790M. Cancer Discov 3:168-81
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
Politi, Katerina; Fan, Pang-Dian; Shen, Ronglai et al. (2010) Erlotinib resistance in mouse models of epidermal growth factor receptor-induced lung adenocarcinoma. Dis Model Mech 3:111-9
Regales, Lucia; Gong, Yixuan; Shen, Ronglai et al. (2009) Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer. J Clin Invest 119:3000-10