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

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.

• Authors: 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
• Journal: Cancer letters (Cancer Lett) Vol. 347 Issue 2 Pg. 204-11 (Jun 01 2014) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 24576621 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Chemical References

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

Topics

• Animals
• Apoptosis (drug effects)
• Class I Phosphatidylinositol 3-Kinases
• Colorectal Neoplasms (enzymology, 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