Synergistic interactions with PI3K inhibition that induce apoptosis.

Elife
Authors
Keywords
Abstract

Activating mutations involving the PI3K pathway occur frequently in human cancers. However, PI3K inhibitors primarily induce cell cycle arrest, leaving a significant reservoir of tumor cells that may acquire or exhibit resistance. We searched for genes that are required for the survival of PI3K mutant cancer cells in the presence of PI3K inhibition by conducting a genome scale shRNA-based apoptosis screen in a mutant human breast cancer cell. We identified 5 genes () whose suppression induced cell death upon PI3K inhibition. We showed that small molecule inhibitors of the PIM2 and ZAK kinases synergize with PI3K inhibition. In addition, using a microscale implementable device to deliver either siRNAs or small molecule inhibitors in vivo, we showed that suppressing these 5 genes with PI3K inhibition induced tumor regression. These observations identify targets whose inhibition synergizes with PI3K inhibitors and nominate potential combination therapies involving PI3K inhibition.

Year of Publication
2017
Journal
Elife
Volume
6
Date Published
2017 05 31
ISSN
2050-084X
DOI
10.7554/eLife.24523
PubMed ID
28561737
PubMed Central ID
PMC5479695
Links
Grant list
R01 CA130988 / CA / NCI NIH HHS / United States
R21 CA177391 / CA / NCI NIH HHS / United States
U01 CA176058 / CA / NCI NIH HHS / United States
U01 CA199253 / CA / NCI NIH HHS / United States