Synergistic interactions with PI3K inhibition that induce apoptosis

Related Experiment Video

Updated: Mar 1, 2026

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
09:18

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death

Published on: December 27, 2016

9.2K

Yaara Zwang1,2, Oliver Jonas3, Casandra Chen1,2

  • 1Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, United States.

Elife
|June 1, 2017
PubMed

Insights

This study identifies five genes crucial for cancer cell survival under PI3K inhibition. Suppressing these genes, along with PI3K inhibitors, leads to tumor regression, suggesting new combination therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Activating mutations in the PI3K pathway are common in human cancers.
  • PI3K inhibitors often induce cell cycle arrest, leading to resistant tumor cell populations.

Purpose of the Study:

  • To identify genes essential for the survival of PI3K-mutant cancer cells during PI3K inhibition.
  • To explore novel therapeutic targets and combination strategies for PI3K-mutant cancers.

Main Methods:

  • Genome-scale shRNA-based apoptosis screen in a PIK3CA-mutant human breast cancer cell line.
  • Validation using small molecule inhibitors of identified kinases (PIM2, ZAK).
  • In vivo studies utilizing a microscale device for siRNA and small molecule inhibitor delivery.

Main Results:

  • Five genes (PIM2, ZAK, TACC1, ZFR, ZNF565) were identified as essential for survival upon PI3K inhibition.
  • Small molecule inhibitors of PIM2 and ZAK kinases synergized with PI3K inhibition.
  • In vivo suppression of these genes combined with PI3K inhibition resulted in tumor regression.

Conclusions:

  • Targeting PIM2, ZAK, TACC1, ZFR, and ZNF565 represents a promising strategy to overcome PI3K inhibitor resistance.
  • Combination therapies involving PI3K inhibitors and inhibitors of these newly identified genes warrant further investigation for cancer treatment.
Keywords:
PI3K inhibitioncancer biologygenome-scale shRNA screenhumanresponse modifying genes

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