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 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

doi:10.1016/j.xcrm.2023.101002

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.

Authors

Priska Auf der Maur¹, Marcel P Trefny², Zora Baumann³, Milica Vulin⁴, Ana Luisa Correia⁴, Maren Diepenbruck³, Nicolas Kramer³, Katrin Volkmann³, Bogdan-Tiberius Preca³, Pedro Ramos⁵, Cedric Leroy⁵, Tobias Eichlisberger⁶, Katarzyna Buczak⁷, Federica Zilli⁴, Ryoko Okamoto⁴, Roland Rad⁸, Michael Rugaard Jensen⁵, Christine Fritsch⁵, Alfred Zippelius², Michael B Stadler⁹, Mohamed Bentires-Alj¹⁰

Affiliations

¹ Tumor Heterogeneity Metastasis and Resistance, Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland. Electronic address: [email protected].
² Cancer Immunology, Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland.
³ Tumor Heterogeneity Metastasis and Resistance, Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland.
⁴ Tumor Heterogeneity Metastasis and Resistance, Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland; Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
⁵ Oncology Research, Novartis Institutes for Biomedical Research, Basel, Switzerland.
⁶ Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
⁷ Proteomics Core Facility, Biozentrum, University of Basel, Basel, Switzerland.
⁸ Institute of Molecular Oncology and Functional Genomics, TUM School of Medicine, Technische Universität München, München, Germany; Center for Translational Cancer Research (TranslaTUM), TUM School of Medicine, Technische Universität München, München, Germany; Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, München, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁹ Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland; Swiss Institute of Bioinformatics, Basel, Switzerland; Faculty of Science, University of Basel, Basel, Switzerland.
¹⁰ Tumor Heterogeneity Metastasis and Resistance, Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland; Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland. Electronic address: [email protected].

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.

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