TY - JOUR
T1 - Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers
AU - Engelman, Jeffrey A.
AU - Chen, Liang
AU - Tan, Xiaohong
AU - Crosby, Katherine
AU - Guimaraes, Alexander R.
AU - Upadhyay, Rabi
AU - Maira, Michel
AU - McNamara, Kate
AU - Perera, Samanthi A.
AU - Song, Youngchul
AU - Chirieac, Lucian R.
AU - Kaur, Ramneet
AU - Lightbown, Angela
AU - Simendinger, Jessica
AU - Li, Timothy
AU - Padera, Robert F.
AU - García-Echeverría, Carlos
AU - Weissleder, Ralph
AU - Mahmood, Umar
AU - Cantley, Lewis C.
AU - Wong, Kwok Kin
N1 - Funding Information:
CCSP-rtTA mice were generously provided by J. Whitsett at the University of Cincinnati. Tet-op-Kras mice were generously provided by H. Varmus (Memorial Sloan-Kettering Cancer Center). LSL-Kras G12D mice were kindly provided by T. Jacks (Massachusetts Institute of Technology). This work was supported by US National Institutes of Health (NIH) K08 grant CA120060-01 (J.A.E.), the American Association for Cancer Research (J.A.E.), the International Association for the Study of Lung Cancer (J.A.E.), NIH prostate cancer grant P01 CA089021 (L.C.C.), NIH pancreatic cancer grant P01 CA117969 (L.C.C.), NIH grant R01 GM41890 (L.C.C.), a Dana-Farber–Harvard Cancer Center Lung Cancer Specialized Program of Research Excellence (SPORE) grant P50 CA090578 (J.A.E. and K.-K.W.) and Dana-Farber–Harvard Cancer Center Gastrointestinal Cancer SPORE grants P50 CA127003 (J.A.E., R.W., U.M. and L.C.C.) and U24-CA092782 (R.W., U.M., A.R.G.). K.-K.W. was supported by NIH grants K08 AG024004, R01 CA122794 and R01 AG2400401; the Joan Scarangello Foundation to Conquer Lung Cancer; the Cecily and Robert Harris Foundation; and the Flight Attendant Medical Research Institute.
PY - 2008/12
Y1 - 2008/12
N2 - Somatic mutations that activate phosphoinositide 3-kinase (PI3K) have been identified in the p110-α catalytic subunit (encoded by PIK3CA). They are most frequently observed in two hotspots: the helical domain (E545K and E542K) and the kinase domain (H1047R). Although the p110-α 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-α 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.
AB - Somatic mutations that activate phosphoinositide 3-kinase (PI3K) have been identified in the p110-α catalytic subunit (encoded by PIK3CA). They are most frequently observed in two hotspots: the helical domain (E545K and E542K) and the kinase domain (H1047R). Although the p110-α 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-α 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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U2 - 10.1038/nm.1890
DO - 10.1038/nm.1890
M3 - Article
C2 - 19029981
AN - SCOPUS:57349194139
SN - 1078-8956
VL - 14
SP - 1351
EP - 1356
JO - Nature medicine
JF - Nature medicine
IS - 12
ER -