Combination PI3K/MEK inhibition promotes tumor apoptosis and regression in PIK3CA wild-type, KRAS mutant colorectal cancer

Cancer Lett. 2014 Jun 1;347(2):204-11. doi: 10.1016/j.canlet.2014.02.018. Epub 2014 Feb 24.

Abstract

PI3K inhibition in combination with other agents has not been studied in the context of PIK3CA wild-type, KRAS mutant cancer. In a screen of phospho-kinases, PI3K inhibition of KRAS mutant colorectal cancer cells activated the MAPK pathway. Combination PI3K/MEK inhibition with NVP-BKM120 and PD-0325901 induced tumor regression in a mouse model of PIK3CA wild-type, KRAS mutant colorectal cancer, which was mediated by inhibition of mTORC1, inhibition of MCL-1, and activation of BIM. These findings implicate mitochondrial-dependent apoptotic mechanisms as determinants for the efficacy of PI3K/MEK inhibition in the treatment of PIK3CA wild-type, KRAS mutant cancer.

Keywords: Colorectal cancer; KRAS; MEK; Mouse model of cancer; PI3K.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Class I Phosphatidylinositol 3-Kinases
  • Colorectal Neoplasms / enzymology
  • Colorectal Neoplasms / pathology*
  • Enzyme Inhibitors / pharmacology
  • Genes, ras*
  • Humans
  • MAP Kinase Kinase Kinases / antagonists & inhibitors*
  • Mice
  • Mice, Inbred C57BL
  • Mutation*
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphoinositide-3 Kinase Inhibitors*

Substances

  • Enzyme Inhibitors
  • Phosphoinositide-3 Kinase Inhibitors
  • Class I Phosphatidylinositol 3-Kinases
  • Pik3ca protein, mouse
  • MAP Kinase Kinase Kinases