Combination PI3K/MEK inhibition promotes tumor apoptosis and regression in PIK3CA wild-type, KRAS mutant colorectal cancer
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Author(s)
Roper, Jatin
Sinnamon, Mark J.
Coffee, Erin M.
Belmont, Peter
Keung, Lily
Georgeon-Richard, Larissa
Wang, Wei Vivian
Faber, Anthony C.
Yun, Jihye
Bronson, Roderick T.
Date Issued
February 2014
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
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
MIT Department
Koch Institute for Integrative Cancer Research at MIT
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Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1016/J.CANLET.2014.02.018
