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

• Published in: Nature medicine Vol. 14; no. 12; pp. 1351 - 1356
• Main Authors: Cantley, Lewis C, Wong, Kwok-Kin, Engelman, Jeffrey A, Chen, Liang, Tan, Xiaohong, Crosby, Katherine, Guimaraes, Alexander R, Upadhyay, Rabi, Maira, Michel, McNamara, Kate, Perera, Samanthi A, Song, Youngchul, Chirieac, Lucian R, Kaur, Ramneet, Lightbown, Angela, Simendinger, Jessica, Li, Timothy, Padera, Robert F, García-Echeverría, Carlos, Weissleder, Ralph, Mahmood, Umar
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.12.2008; Nature Publishing Group
• Subjects: Animals; Antimitotic agents; Antineoplastic agents; Biomedical and Life Sciences; Biomedicine; Cancer Research; Care and treatment; Cellular biology; Class I Phosphatidylinositol 3-Kinases; Computed tomography; Dosage and administration; Down-Regulation - drug effects; Emissions; Gene Expression Regulation, Neoplastic - drug effects; Genetic aspects; Health aspects; Infectious Diseases; Inhibitors; Kinases; letter; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - enzymology; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Mammals; MAP Kinase Signaling System - drug effects; Metabolic Diseases; Mice; Mice, Transgenic; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinase Kinases - metabolism; Molecular Medicine; Mutants; Mutation; Mutation - genetics; Neurosciences; Oncology; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Protein Kinase Inhibitors - therapeutic use; Protein kinases; Proto-Oncogene Proteins p21(ras) - genetics; Proto-Oncogene Proteins p21(ras) - metabolism; Rodents; Signal transduction; Tumors; United States
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.1890

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.