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

Jatin Roper, Mark J. Sinnamon, Erin M. Coffee, Peter Belmont, Lily Keung, Larissa Georgeon-Richard, Wei Vivian Wang, Anthony C. Faber, Jihye Yun, Ömer H. Yilmaz, Roderick T. Bronson, Eric S. Martin, Philip N. Tsichlis, Kenneth E. Hung

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

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.

Original languageEnglish
Pages (from-to)204-211
Number of pages8
JournalCancer Letters
Volume347
Issue number2
DOIs
StatePublished - 1 Jun 2014
Externally publishedYes

Keywords

  • Colorectal cancer
  • KRAS
  • MEK
  • Mouse model of cancer
  • PI3K

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