Synergistic interactions with PI3K inhibition that induce apoptosis
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- May 31, 2017
- Source ID
- 10.7554/elife.24523
Entities
People
- Anthony Letai
- Casandra Chen
- David E Root
- Federica Piccioni
- Hai-tsang Huang
- Jinhua Wang
- John G Doench
- Joyce O'connell
- Li Tan
- Matthew Whitman
- Michael J Cima
- Mihir Doshi
- Mikael L. Rinne
- Nathanael Gray
- Oliver Jonas
- Patrick D Bhola
- Robert S. Langer, Jr.
- William C Hahn
- Yaara Zwang
- Young Jin Ham
Organizations
- Congressionally Directed Medical Research Programs
- Dana–Farber Cancer Institute
- Harvard Medical School
- Massachusetts Institute of Technology
- National Cancer Institute
- National Institutes of Health