Synergistic interactions with PI3K inhibition that induce apoptosis
Name
Cima_Synergistic interactions.pdf
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1.02 MB
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Checksum (MD5)
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Author(s)
Zwang, Yaara
Chen, Casandra
Rinne, Mikael L
Doench, John G
Piccioni, Federica
Tan, Li
Huang, Hai-Tsang
Wang, Jinhua
Ham, Young Jin
O'Connell, Joyce
Date Issued
May 2017
Journal
eLife
Publisher
eLife Sciences Publications, Ltd
Citation
Zwang, Yaara et al. “Synergistic Interactions with PI3K Inhibition That Induce Apoptosis.” eLife 6 (May 2017): e24523 © 2017 Zwang et al
Version
Final published version
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.
MIT Department
Massachusetts Institute of Technology. Department of Chemical Engineering
Massachusetts Institute of Technology. Department of Materials Science and Engineering
Koch Institute for Integrative Cancer Research at MIT
Terms of Use
Creative Commons Attribution 4.0 International License
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DOI of Published Version
https://doi.org/10.7554/eLife.24523
