EGFR mutant lung cancer is a subset of lung cancer with unique biological and clinical features. Over 70% of patients whose lung cancers harbor specific mutations within the exons encoding the tyrosine kinase domain of EGFR experience radiographic responses to the selective EGFR tyrosine kinase inhibitors (TKIs), gefitinib (Iressa) or eriotinib (Tarceva), and overall median survival is about 30 months. However, no patients are cured. After about one year, acquired resistance develops. In previous work, we showed that in addition to primary drug-sensitive EGFR mutations, tumor cells from more than half of patients with such "acquired resistance" contain a recurrent second-site mutation (T790M) in the EGFR kinase domain. We also demonstrated using mouse models of lung cancer that T790M-mediated resistance could be overcome by a novel combination ofthe second-generation EGFR TKI, afatinib (BIBW2992), and the anti-EGFR antibody, cetuximab. A Phase IB clinical trial ofthis combination in humans, based upon our data, has now shown unprecedented activity in this patient cohort, with a 95% clinical benefit rate and a 35% confirmed radiographic response rate. The clinical findings have stimulated new and critical biological questions to address. Here, based upon promising new preliminary data, we aim to 1) elucidate the role of HER2 in mediating sensitivity of T790M-harboring EGFR mutant lung cancer cells to afatinib/cetuximab, and 2) identify in EGFR mutant kinases intrinsic regulatory domains required for full kinase function. An improved understanding of mechanisms and modulators of sensitivity and resistance to EGFR inhibitors will hopefully allow us to treat/suppress the development of progressive disease and provide new insights into the biology of cancers driven by EGFR or other mutant receptor tyrosine kinases.

Public Health Relevance

Lung cancers are America's leading cancer killers, responsible for 158,000 deaths this year. This grant addresses the two most critical roadblocks to improving the care and curability of persons with these illnesses: (1) understanding how cancers spread (metastasis) and (2) the lack of highly effective medicines to prevent spread or to eradicate cancers that have spread from the lung.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA129243-07
Application #
8563895
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
7
Fiscal Year
2013
Total Cost
$366,666
Indirect Cost
$126,879
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Yu, Helena A; Arcila, Maria E; Harlan Fleischut, Megan et al. (2014) Germline EGFR T790M mutation found in multiple members of a familial cohort. J Thorac Oncol 9:554-8
Meador, Catherine B; Micheel, Christine M; Levy, Mia A et al. (2014) Beyond histology: translating tumor genotypes into clinically effective targeted therapies. Clin Cancer Res 20:2264-75
Valiente, Manuel; Obenauf, Anna C; Jin, Xin et al. (2014) Serpins promote cancer cell survival and vascular co-option in brain metastasis. Cell 156:1002-16
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
Rekhtman, Natasha; Borsu, Laetitia; Reva, Boris et al. (2014) Unsuspected collision of synchronous lung adenocarcinomas: a potential cause of aberrant driver mutation profiles. J Thorac Oncol 9:e1-3
Yu, H A; Arcila, M E; Hellmann, M D et al. (2014) Poor response to erlotinib in patients with tumors containing baseline EGFR T790M mutations found by routine clinical molecular testing. Ann Oncol 25:423-8
Lovly, Christine M; McDonald, Nerina T; Chen, Heidi et al. (2014) Rationale for co-targeting IGF-1R and ALK in ALK fusion-positive lung cancer. Nat Med 20:1027-34
Yu, Helena A; Riely, Gregory J; Lovly, Christine M (2014) Therapeutic strategies utilized in the setting of acquired resistance to EGFR tyrosine kinase inhibitors. Clin Cancer Res 20:5898-907
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
Haq, Rizwan; Fisher, David E; Widlund, Hans R (2014) Molecular pathways: BRAF induces bioenergetic adaptation by attenuating oxidative phosphorylation. Clin Cancer Res 20:2257-63

Showing the most recent 10 out of 59 publications