Requirement for interaction of PI3-kinase p110α with RAS in lung tumor maintenance

Cancer Cell. 2013 Nov 11;24(5):617-30. doi: 10.1016/j.ccr.2013.09.012.


RAS proteins directly activate PI3-kinases. Mice bearing a germline mutation in the RAS binding domain of the p110α subunit of PI3-kinse are resistant to the development of RAS-driven tumors. However, it is unknown whether interaction of RAS with PI3-kinase is required in established tumors. The need for RAS interaction with p110α in the maintenance of mutant Kras-driven lung tumors was explored using an inducible mouse model. In established tumors, removal of the ability of p110α to interact with RAS causes long-term tumor stasis and partial regression. This is a tumor cell-autonomous effect, which is improved significantly by combination with MEK inhibition. Total removal of p110α expression or activity has comparable effects, albeit with greater toxicities.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / enzymology*
  • Adenocarcinoma / pathology
  • Animals
  • Antineoplastic Agents, Hormonal / pharmacology
  • Class I Phosphatidylinositol 3-Kinases / chemistry
  • Class I Phosphatidylinositol 3-Kinases / genetics
  • Class I Phosphatidylinositol 3-Kinases / metabolism*
  • Disease Progression
  • Humans
  • Lung / pathology
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / enzymology*
  • Lung Neoplasms / pathology
  • MAP Kinase Signaling System / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mutation
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Pyridones / pharmacology
  • Pyrimidinones / pharmacology
  • Tamoxifen / pharmacology
  • Tumor Burden


  • Antineoplastic Agents, Hormonal
  • Pyridones
  • Pyrimidinones
  • Tamoxifen
  • trametinib
  • 1-phosphatidylinositol 3-kinase p110 subunit, mouse
  • Class I Phosphatidylinositol 3-Kinases
  • Mitogen-Activated Protein Kinases
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)