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

Author(s)
Roper, Jatin; Sinnamon, Mark J.; Coffee, Erin M.; Belmont, Peter; Keung, Lily; ... Show more
Thumbnail
Downloadnihms-615364.pdf (1.304Mb)
PUBLISHER_CC
Terms of use
Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/
Metadata
Show full item record
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: PI3K; MEK; KRAS; Colorectal cancer; Mouse model of cancer
Date issued
2014-02
URI
http://hdl.handle.net/1721.1/117053
Department
David H. Koch Institute for Integrative Cancer Research at MIT
Journal
Cancer Letters
Publisher
Elsevier
Citation
Roper, Jatin et al. “Combination PI3K/MEK Inhibition Promotes Tumor Apoptosis and Regression in PIK3CA Wild-Type, KRAS Mutant Colorectal Cancer.” Cancer Letters 347, 2 (June 2014): 204–211 © 2014 Elsevier Ireland Ltd
Version: Author's final manuscript
ISSN
0304-3835
Collections