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Elife. 2017 May 31;6. pii: e24523. doi: 10.7554/eLife.24523.

Synergistic interactions with PI3K inhibition that induce apoptosis.

Author information

1
Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, United States.
2
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, United States.
3
The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, United States.
4
Department of Cancer Biology, Dana Farber Cancer Institute, Boston, United States.
5
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, United States.
6
Department of Materials Science, Massachusetts Institute of Technology, Cambridge, United States.
7
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, United States.
8
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, United States.

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 PIK3CA mutant human breast cancer cell. We identified 5 genes (PIM2, ZAK, TACC1, ZFR, ZNF565) 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.

KEYWORDS:

PI3K inhibition; cancer biology; genome-scale shRNA screen; human; response modifying genes

PMID:
28561737
PMCID:
PMC5479695
DOI:
10.7554/eLife.24523
[Indexed for MEDLINE]
Free PMC Article

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