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Cancer Discov. 2014 Mar;4(3):334-47. doi: 10.1158/2159-8290.CD-13-0611. Epub 2014 Jan 16.

Rapid induction of apoptosis by PI3K inhibitors is dependent upon their transient inhibition of RAS-ERK signaling.

Author information

1
1Program in Molecular Pharmacology; 2Human Oncology and Pathogenesis Program; 3Program in Cell Biology, Memorial Sloan-Kettering Cancer Center; 4Weill Cornell Medical College, New York, New York; and 5Bayer HealthCare, Global Drug Discovery, Berlin, Germany.

Abstract

The effects of selective phosphoinositide 3-kinase (PI3K) and AKT inhibitors were compared in human tumor cell lines in which the pathway is dysregulated. Both caused inhibition of AKT, relief of feedback inhibition of receptor tyrosine kinases, and growth arrest. However, only the PI3K inhibitors caused rapid induction of cell death. In seeking a mechanism for this phenomenon, we found that PI3K inhibition, but not AKT inhibition, causes rapid inhibition of wild-type RAS and of RAF-MEK-ERK signaling. Inhibition of RAS-ERK signaling is transient, rebounding a few hours after drug addition, and is required for rapid induction of apoptosis. Combined MEK and AKT inhibition also promotes cell death, and in murine models of HER2(+) cancer, either pulsatile PI3K inhibition or combined MEK and AKT inhibition causes tumor regression. We conclude that PI3K is upstream of RAS and AKT and that pulsatile inhibition of both pathways is sufficient for effective antitumor activity.

PMID:
24436048
PMCID:
PMC4049524
DOI:
10.1158/2159-8290.CD-13-0611
[Indexed for MEDLINE]
Free PMC Article

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