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

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

Author information

1
Tufts Medical Center, Division of Gastroenterology, Department of Medicine, Boston, MA, United States; Tufts Medical Center, Molecular Oncology Research Institute, Boston, MA, United States. Electronic address: jroper@tuftsmedicalcenter.org.
2
Massachusetts General Hospital, Center for Systems Biology, Boston, MA, United States.
3
Massachusetts General Hospital Cancer Center, Boston, MA, United States.
4
Celgene, Discovery, Oncology Research, San Diego, CA, United States.
5
Tufts Medical Center, Molecular Oncology Research Institute, Boston, MA, United States.
6
Tufts Medical Center, Division of Gastroenterology, Department of Medicine, Boston, MA, United States.
7
Weill Cornell Medical College and New York-Presbyterian Hospital, Department of Medicine, New York, NY, United States.
8
The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States.
9
Dana Farber/Harvard Cancer Center, Harvard Medical School, Boston, MA, United States.
10
Pfizer Biotherapeutics Clinical Research, Cambridge, MA, United States.

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

PMID:
24576621
PMCID:
PMC4118771
DOI:
10.1016/j.canlet.2014.02.018
[Indexed for MEDLINE]
Free PMC Article

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