N-acetylcysteine overcomes NF1 loss-driven resistance to PI3K α inhibition in breast cancer

Cell Rep Med. 2023 Apr 4:101002. doi: 10.1016/j.xcrm.2023.101002. Online ahead of print.ABSTRACTA 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.PMID:37044095 | DOI:10.1016/j.xcrm.2023.101002

Source: Genomics Proteomics ... - April 12, 2023 Category: Genetics & Stem Cells Authors: Priska Auf der Maur Marcel P Trefny Zora Baumann Milica Vulin Ana Luisa Correia Maren Diepenbruck Nicolas Kramer Katrin Volkmann Bogdan-Tiberius Preca Pedro Ramos Cedric Leroy Tobias Eichlisberger Katarzyna Buczak Federica Zilli Ryoko Okamoto Roland Rad M Source Type: research