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

ABSTRACT: Breast cancer is the second most common cancer type worldwide, representing 25% of all cancers in women. PIK3CA is one of the most frequently mutated genes in breast cancer and mutations result in constitutive activation of the PI3K/mTOR pathway. More than 30 inhibitors against PI3K/mTOR are being tested in clinical trials, however, resistance mechanisms evolve frequently resulting in disease progression. The aim of our study was to investigate PIK3CA collaborative mutations that result in resistance to BYL719, a PI3Kα selective inhibitor. For this purpose, we used a genome-wide PiggyBac transposon mediated mutagenesis screen in a PIK3CAH1047R mutated murine tumor model. One of the tumor suppressor genes discovered was neurofibromin 1 (NF1). Using shRNA-mediated knockdown and CRISPR/Cas9-mediated knockout of NF1 in murine and human PIK3CAH1047R cell lines and a patient derived xenograft organoid model, we found that NF1 loss reduces sensitivity to PI3Kα inhibition. Additionally, we find that loss of NF1 correlates with enhanced glycolysis and lower levels of ROS. Unexpectedly, treatment with NAC sensitized NF1 KO cells to PI3K inhibition in vitro, and in vivo. Global phospho-proteomics indicated that the combination with NAC enhances the inhibitory effect of PI3K inhibition on mTOR signaling, which inhibits proliferation of NF1 KO tumor cells. This raises the interesting possibility to combine PI3K inhibition with NAC especially in NF1 loss tumors

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Katarzyna Buczak

LAB HEAD: Alexander Schmidt

PROVIDER: PXD034644 | Pride | 2023-03-30

REPOSITORIES: Pride

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			Action	DRS
	001_PM002_PO4_D22.raw	Raw
	001_PM003_2DTMT_G21.raw	Raw
	002_PM002_PO4_D22.raw	Raw
	002_PM003_2DTMT_G21.raw	Raw
	003_PM002_PO4_D22.raw	Raw

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