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

ABSTRACT: A genome-wide PiggyBac transposon-mediated screen and a resistance screen in a PIK3CA^H1047R-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 PIK3CA^H1047R 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 h

SUBMITTER: Auf der Maur P 

PROVIDER: S-EPMC10140479 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature