Synergistic interactions with PI3K inhibition that induce apoptosis

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

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.

MeSH terms

  • Animals
  • Apoptosis*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Disease Models, Animal
  • Drug Synergism*
  • Enzyme Inhibitors / metabolism*
  • Humans
  • MAP Kinase Kinase Kinases
  • Mice, SCID
  • Neoplasms, Experimental / therapy
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Kinases / metabolism*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Transplantation, Heterologous
  • Treatment Outcome

Substances

  • Enzyme Inhibitors
  • PIM2 protein, human
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Protein Kinases
  • Protein-Serine-Threonine Kinases
  • MAP Kinase Kinase Kinases
  • MAP3K20 protein, human