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Can I read N -acetylcysteine overcomes NF1 loss-driven resistance to PI3Kα inhibition in breast cancer on EtoBox?
N -acetylcysteine overcomes NF1 loss-driven resistance to PI3Kα inhibition in breast cancer by 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; Michael Rugaard Jensen; Christine Fritsch; Alfred Zippelius; Michael B. Stadler; Mohamed Bentires-Alj is a Medicine article available to read on EtoBox.
What is N -acetylcysteine overcomes NF1 loss-driven resistance to PI3Kα inhibition in breast cancer about?
## Summary 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.
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- Author
- 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; Michael Rugaard Jensen; Christine Fritsch; Alfred Zippelius; Michael B. Stadler; Mohamed Bentires-Alj
- Publisher
- Elsevier
- Published
- 2023
- Language
- EN
- Field
- Medicine (Health Sciences)