N-acetylcysteine overcomes NF1 loss-driven resistance to PI3Kα inhibition in breast cancer
Priska Auf der Maur, Marcel P. Trefny, Zora Baumann, Milica Vulin, Ana Luísa Correia, Maren Diepenbruck, Nicolas Kramer, Katrin Volkmann, Bogdan‐Tiberius Preca, Pedro Marques Ramos, Cédric Leroy, Tobias Eichlisberger, Katarzyna Buczak, Federica Zilli, Ryoko Okamoto, Roland Rad, Michael Rugaard Jensen, Christine Fritsch, Alfred Zippelius, Michael Stadler, Mohamed Bentires‐Alj
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 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.