N-acetylcysteine overcomes NF1 loss-driven resistance to PI3Kα inhibition in breast cancer

Cell Rep Med. 2023 Apr 18;4(4):101002. doi: 10.1016/j.xcrm.2023.101002. Epub 2023 Apr 11.

Abstract

A genome-wide PiggyBac transposon-mediated screen and a resistance screen in a PIK3CAH1047R-mutated murine tumor model reveal NF1 loss in mammary tumors resistant to the phosphatidylinositol 3-kinase α (PI3Kα)-selective inhibitor alpelisib. Depletion of NF1 in PIK3CAH1047R breast cancer cell lines and a patient-derived organoid model shows that NF1 loss reduces sensitivity to PI3Kα inhibition and correlates with enhanced glycolysis and lower levels of reactive oxygen species (ROS). Unexpectedly, the antioxidant N-acetylcysteine (NAC) sensitizes NF1 knockout cells to PI3Kα inhibition and reverts their glycolytic phenotype. Global phospho-proteomics indicates that combination with NAC enhances the inhibitory effect of alpelisib on mTOR signaling. In public datasets of human breast cancer, we find that NF1 is frequently mutated and that such mutations are enriched in metastases, an indication for which use of PI3Kα inhibitors has been approved. Our results raise the attractive possibility of combining PI3Kα inhibition with NAC supplementation, especially in patients with drug-resistant metastases associated with NF1 loss.

Keywords: PI3K alpha inhibition; breast cancer; combination therapy; resistance; transposon screen.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / pharmacology
  • Animals
  • Breast Neoplasms* / drug therapy
  • Breast Neoplasms* / genetics
  • Breast Neoplasms* / metabolism
  • Class I Phosphatidylinositol 3-Kinases / genetics
  • Female
  • Humans
  • Mice
  • Phosphatidylinositol 3-Kinase
  • Phosphatidylinositol 3-Kinases / genetics

Substances

  • Alpelisib
  • Phosphatidylinositol 3-Kinase
  • Acetylcysteine
  • Class I Phosphatidylinositol 3-Kinases
  • Phosphatidylinositol 3-Kinases