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Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers

Abstract

Somatic mutations that activate phosphoinositide 3-kinase (PI3K) have been identified in the p110-α 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-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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Figure 1: Development of a Tet-inducible PIK3CA H1047R mouse model of lung tumorigenesis.
Figure 2: NVP-BEZ235 downregulates PI3K signaling in p110-α H1047R–induced lung tumors and leads to rapid tumor regression.
Figure 3: PI3K signaling is needed for Kras-induced tumorigenesis but not tumor maintenance.
Figure 4: Combined PI3K and MEK inhibition shrinks Kras G12D induced lung tumors.

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Acknowledgements

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.

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Contributions

J.A.E., L.C., L.C.C. and K.-K.W. developed the hypotheses, designed the experiments and wrote the manuscript. L.C. and J.A.E. executed most of the experiments other than immunohistochemistry and PET imaging. X.T., S.A.P., K.M., Y.S., R.K. and T.L. assisted with mouse work, dissections and drug treatments. K.C., A.L. and J.S. performed immunohistochemistry. A.R.G., R.U., R.W. and U.M. performed the mouse imaging studies. C.G.-E. and M.M. provided NVP-BEZ235 as well as guidance for its proper use and insights regarding experimental design. L.R.C. and R.F.P. provided pathological review of histology and immunohistochemistry.

Corresponding authors

Correspondence to Lewis C Cantley or Kwok-Kin Wong.

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Competing interests

C.G.-E. and M.M. are employees and stockholders of Novartis.

Supplementary information

Supplementary Text and Figures

Supplementary Figs. 1—6 and Supplementary Methods (PDF 965 kb)

Supplementary Movie 1

Reconstruction three-dimensional PET-CT images of a mouse with a p110-α H1047R–induced lung tumor before and after treatment with NVP-BEZ 235. The 18FDG PET-CT studies were obtained before and after treatment with NVP-BEZ235 35 mg/kg per day for four days. (MOV 2033 kb)

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Engelman, J., Chen, L., Tan, X. et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med 14, 1351–1356 (2008). https://doi.org/10.1038/nm.1890

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