Display Settings:

Format

Send to:

Choose Destination
See comment in PubMed Commons below
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

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

Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

KEYWORDS:

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

PMID:
24576621
[PubMed - indexed for MEDLINE]
PMCID:
PMC4118771
Free PMC Article

Images from this publication.See all images (6)Free text

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science Icon for PubMed Central
    Loading ...
    Write to the Help Desk