期刊
NATURE MEDICINE
卷 14, 期 12, 页码 1351-1356出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.1890
关键词
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资金
- US National Institutes of Health (NIH) [CA120060-01]
- American Association for Cancer Research
- International Association for the Study of Lung Cancer
- NIH [CA089021, P01 CA117969, R01 GM41890, K08 AG024004, R01 CA122794, R01 AG2400401]
- Dana-Farber-Harvard Cancer Center Lung Cancer Specialized Program of Research Excellence (SPORE) [P50 CA090578]
- Dana-Farber-Harvard Cancer Center Gastrointestinal Cancer SPORE [P50 CA127003, U24-CA092782]
- Joan Scarangello Foundation to Conquer Lung Cancer
- Cecily and Robert Harris Foundation
- Flight Attendant Medical Research Institute
Somatic mutations that activate phosphoinositide 3-kinase (PI3K) have been identified in the p110-alpha catalytic subunit (encoded by PIK3CA)(1). They are most frequently observed in two hotspots: the helical domain (E545K and E542K) and the kinase domain (H1047R). Although the p110-alpha mutants are transforming in vitro, their oncogenic potential has not been assessed in genetically engineered mouse models. Furthermore, clinical trials with PI3K inhibitors have recently been initiated, and it is unknown if their efficacy will be restricted to specific, genetically defined malignancies. In this study, we engineered a mouse model of lung adenocarcinomas initiated and maintained by expression of p110-alpha H1047R. Treatment of these tumors with NVP-BEZ235, a dual pan-PI3K and mammalian target of rapamycin (mTOR) inhibitor in clinical development, led to marked tumor regression as shown by positron emission tomography-computed tomography, magnetic resonance imaging and microscopic examination. In contrast, mouse lung cancers driven by mutant Kras did not substantially respond to single-agent NVP-BEZ235. However, when NVP-BEZ235 was combined with a mitogen-activated protein kinase kinase (MEK) inhibitor, ARRY-142886, there was marked synergy in shrinking these Kras-mutant cancers. These in vivo studies suggest that inhibitors of the PI3K-mTOR pathway may be active in cancers with PIK3CA mutations and, when combined with MEK inhibitors, may effectively treat KRAS mutated lung cancers.
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