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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE207515 | GEO | 2023/03/16

REPOSITORIES: GEO

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

Project description: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

2023-03-30 | PXD034644 | Pride

N-acetylcysteine overcomes NF1-loss driven resistance to PI3K alpha inhibition in breast cancer [RNAseq_WAP]

Project description:The aim of our study was to investigate PIK3CA collaborative mutations that result in resistance to BYL719, a PI3Kα selective inhibitor. 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. By looking at differentially expressed genes we wanted to investigate the effect of NF1 KO in T47D cells and if they respond differentially to BYL719 compared to the T47D CTRL cells.

2023-03-16 | GSE207512 | GEO

N-acetylcysteine overcomes NF1-loss driven resistance to PI3K alpha inhibition in breast cancer [ATAC-seq]

2023-03-16 | GSE207513 | GEO

N-acetylcysteine overcomes NF1-loss driven resistance to PI3K alpha inhibition in breast cancer [T47D RNA-seq]

2023-03-16 | GSE207514 | GEO

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

Project description:N-acetylcysteine overcomes NF1-loss driven resistance to PI3K alpha inhibition in breast cancer

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N-acetylcysteine overcomes NF1-loss driven resistance to PI3K alpha inhibition in breast cancer [RNAseq_WAP]

Project description:N-acetylcysteine overcomes NF1-loss driven resistance to PI3K alpha inhibition in breast cancer [RNAseq_WAP]

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N-acetylcysteine overcomes NF1-loss driven resistance to PI3K alpha inhibition in breast cancer [ATAC-seq]

Project description:N-acetylcysteine overcomes NF1-loss driven resistance to PI3K alpha inhibition in breast cancer [ATAC-seq]

| PRJNA855954 | ENA

N-acetylcysteine overcomes NF1-loss driven resistance to PI3K alpha inhibition in breast cancer [T47D RNA-seq]

Project description:N-acetylcysteine overcomes NF1-loss driven resistance to PI3K alpha inhibition in breast cancer [T47D RNA-seq]

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Inhibition of PI3K/Akt/mTOR overcomes cisplatin resistance in the triple negative breast cancer cell line HCC38.

Project description:Widely established targeted therapies directed at triple negative breast cancer (TNBC) are missing. Classical chemotherapy remains the systemic treatment option. Cisplatin has been tested in TNBC but bears the disadvantage of resistance development. The purpose of this study was to identify resistance mechanisms in cisplatin-resistant TNBC cell lines and select targeted therapies based on these findings.The TNBC cell lines HCC38 and MDA-MB231 were subjected to intermittent cisplatin treatment resulting in the 3.5-fold cisplatin-resistant subclone HCC38CisR and the 2.1-fold more resistant MDA-MB231CisR. Activation of pro-survival pathways was explored by immunostaining of phospho-receptor tyrosine kinases. Targeted therapies (NVP-AEW541, lapatinib and NVP-BEZ235) against activated pathways were investigated regarding cancer cell growth and cisplatin sensitivity.In HCC38CisR and MDA-MB231CisR, phosphorylation of epidermal growth factor receptor (EGFR) and insulin-like growth factor 1 receptor (IGF1R) was observed. In HCC38CisR, treatment with NVP-AEW541 increased potency of lapatinib almost seven-fold, but both compounds could not restore cisplatin sensitivity. However, the dual phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor NVP-BEZ235 acted synergistically with cisplatin in HCC38CisR and fully restored cisplatin sensitivity. Similarly, NVP-BEZ235 increased cisplatin potency in MDA-MB231CisR. Furthermore, NVP-AEW541 in combination with lapatinib restored cisplatin sensitivity in MDA-MB231CisR.Simultaneous inhibition of EGFR and IGF1R in cisplatin-resistant TNBC cell lines was synergistic regarding inhibition of proliferation and induction of apoptosis. Co-treatment with NVP-BEZ235 or with a combination of NVP-AEW541 and lapatinib restored cisplatin sensitivity and may constitute a targeted treatment option for cisplatin-resistant TNBC.

| S-EPMC5670521 | biostudies-literature

V-ATPase inhibition overcomes trastuzumab resistance in breast cancer.

Project description:The HER2 oncogene targeting drug trastuzumab shows remarkable efficacy in patients overexpressing HER2. However acquired or primary resistance develops in most of the treated patients why alternative treatment strategies are strongly needed. As endosomal sorting and recycling are crucial steps for HER2 activity and the vacuolar H⁺-ATPase (V-ATPase) is an important regulator of endocytotic trafficking, we proposed that targeting V-ATPase opens a new therapeutic strategy against trastuzumab-resistant tumor cells in vitro and in vivo. V-ATPase inhibition with archazolid, a novel inhibitor of myxobacterial origin, results in growth inhibition, apoptosis and impaired HER2 pro-survival signaling of the trastuzumab-resistant cell line JIMT-1. This is accompanied by a decreased expression on the plasma membrane and accumulation of HER2 in the cytosol, where it colocalizes with endosomes, lysosomes and autophagosomes. Importantly, microscopic analysis of JIMT-1 xenograft tumor tissue of archazolid treated mice confirms the defect in HER2-recycling which leads to reduced tumor growth. These results suggest that V-ATPase inhibition by archazolid induces apoptosis and inhibits growth of trastuzumab-resistant tumor cells by retaining HER2 in dysfunctional vesicles of the recycling pathway and consequently abrogates HER2-signaling in vitro as well as in vivo. V-ATPase inhibition is thus suggested as a promising strategy for treatment of trastuzumab-resistant tumors.

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