title: 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-alpha 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-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.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
authors.forename: Liang
authors.initials: L
authors.lastname: Chen
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Tan
authors.forename: Katherine
authors.initials: K
authors.lastname: Crosby
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Guimaraes
authors.forename: Rabi
authors.initials: R
authors.lastname: Upadhyay
authors.forename: Michel
authors.initials: M
authors.lastname: Maira
authors.forename: Kate
authors.initials: K
authors.lastname: McNamara
authors.forename: Samanthi A
authors.initials: SA
authors.lastname: Perera
authors.forename: Youngchul
authors.initials: Y
authors.lastname: Song
authors.forename: Lucian R
authors.initials: LR
authors.lastname: Chirieac
authors.forename: Ramneet
authors.initials: R
authors.lastname: Kaur
authors.forename: Angela
authors.initials: A
authors.lastname: Lightbown
authors.forename: Jessica
authors.initials: J
authors.lastname: Simendinger
authors.forename: Timothy
authors.initials: T
authors.lastname: Li
authors.forename: Robert F
authors.initials: RF
authors.lastname: Padera
authors.forename: Carlos
authors.initials: C
authors.lastname: García-Echeverría
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.forename: Umar
authors.initials: U
authors.lastname: Mahmood
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
mesh_terms: D000818:Animals; D058534:Class I Phosphatidylinositol 3-Kinases; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras)