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

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.

Pubmed ID: 19029981

Authors

  • Engelman JA
  • Chen L
  • Tan X
  • Crosby K
  • Guimaraes AR
  • Upadhyay R
  • Maira M
  • McNamara K
  • Perera SA
  • Song Y
  • Chirieac LR
  • Kaur R
  • Lightbown A
  • Simendinger J
  • Li T
  • Padera RF
  • García-Echeverría C
  • Weissleder R
  • Mahmood U
  • Cantley LC
  • Wong KK

Journal

Nature medicine

Publication Data

December 5, 2008

Associated Grants

  • Agency: NIA NIH HHS, Id: K08 AG024004
  • Agency: NCI NIH HHS, Id: K08 CA120060
  • Agency: NCI NIH HHS, Id: K08 CA120060-01
  • Agency: NCI NIH HHS, Id: K08 CA120060-03
  • Agency: NCI NIH HHS, Id: P01 CA089021
  • Agency: NCI NIH HHS, Id: P01 CA089021
  • Agency: NCI NIH HHS, Id: P01 CA089021-07
  • Agency: NCI NIH HHS, Id: P01 CA117969
  • Agency: NCI NIH HHS, Id: P01 CA117969-040002
  • Agency: NCI NIH HHS, Id: P50 CA090578
  • Agency: NCI NIH HHS, Id: P50 CA090578
  • Agency: NCI NIH HHS, Id: P50 CA090578-060009
  • Agency: NCI NIH HHS, Id: P50 CA090578-060010
  • Agency: NCI NIH HHS, Id: P50 CA127003
  • Agency: NIA NIH HHS, Id: R01 AG2400401
  • Agency: NCI NIH HHS, Id: R01 CA122794
  • Agency: NCI NIH HHS, Id: R01 CA122794
  • Agency: NCI NIH HHS, Id: R01 CA122794-03
  • Agency: NCI NIH HHS, Id: R01 CA137008
  • Agency: NCI NIH HHS, Id: R01 CA137008-01
  • Agency: NIGMS NIH HHS, Id: R01 GM036624
  • Agency: NIGMS NIH HHS, Id: R01 GM036624-22
  • Agency: NIGMS NIH HHS, Id: R01 GM041890
  • Agency: NIGMS NIH HHS, Id: R01 GM056203
  • Agency: NIGMS NIH HHS, Id: R01 GM056203-12
  • Agency: NIGMS NIH HHS, Id: R01 GM41890
  • Agency: NIGMS NIH HHS, Id: R37 GM041890
  • Agency: NIGMS NIH HHS, Id: R37 GM041890-20
  • Agency: NCI NIH HHS, Id: U24-CA092782

Mesh Terms

  • Animals
  • Down-Regulation
  • Gene Expression Regulation, Neoplastic
  • Lung Neoplasms
  • MAP Kinase Signaling System
  • Mice
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinase Kinases
  • Mutation
  • Phosphatidylinositol 3-Kinases
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins p21(ras)