Acar, S. | bioRxiv Science

bioRxiv2026

Multi-omics integration of malignant peripheral nerve sheath tumors identifies potential targets based on chromosome 8q status

BackgroundChromosome 8q (chr8q) copy number gain is associated with high-grade transformation in malignant peripheral nerve sheath tumors (MPNST), an aggressive soft tissue tumor with poor outcomes in the high-risk and metastatic settings. Although chr8q gain is associated with inferior overall survival in patients with MPNST, standard of care therapies do not currently consider stratification by genomic features, including chr8q status. MethodsWe employed a proteogenomic approach to characterize proteomic and transcriptional programs associated with chr8q and nominate drug targets for potential treatment stratification based on chr8q status. We leveraged our growing library of fully characterized MPNST patient-derived xenografts (PDX) and collected LC-MS/MS global and phospho-proteomics measurements for six of these samples. We then integrated these data with transcriptomics and copy number data to identify molecular changes that are correlated with chr8q copy number. We nominated pathways, transcription factors, and kinases that were differentially active in chr8q gain samples and posited that these samples would respond differently to drugs compared to chr8q wildtype samples. We then tested this hypothesis in vitro. ResultsOur results suggest that the chr8q gene MYC may be a key driver of downstream effects that can be targetable with inhibitors of PLK1. Conversely, EGFR inhibition may be more effective in MYC-diploid MPNSTs than those with MYC gain. These results nominate candidate pathways and drug classes to target tumor heterogeneity in MPNST through the proteogenomic integration and drug sensitivity prediction in distinct tumor subpopulations. ConclusionsWe show that integration of multiomics data can identify specific drug therapies to selectively target tumor cells based on chr8q copy number. This not only provides novel avenues for drug nomination going forward but also may be important for stratifying treatment and mitigating resistance in heterogeneous tumors.

cancer biology↗

bioRxiv2020

Combined inhibition of KDM6A/B and HDACs exacerbates integrated stress response and mediates therapeutic effects in IDH1-mutant glioma

BackgroundIDH1/2-mutant gliomas are primary brain tumors for which curative treatments are lacking. Mutant IDH-dependent 2-hydroxyglutarate (2-HG) accumulation leads to DNA and histone hypermethylation. Based on this distinct phenotype, we interrogated epigenetic dependencies of IDH-mutant glioma that can be targeted therapeutically. MethodsWe conducted a chemical screen targeting chromatin modifiers in patient derived IDH1-mutant GBM cells. We investigated mechanisms of action of compound hits and their combinations through cell-based functional assays, live-cell imaging, Western blot, CRISPR knockout, RNA-seq and ChIP experiments. The therapeutic concept was validated in vivo using chemical inhibitors GSK-J4 and Belinostat in an orthotopic GBM model. ResultsWe identified the H3K27me3 demethylase (KDM6) inhibitor GSK-J4 and histone deacetylase inhibitor Belinostat as potent, genotype-selective agents against IDH1-mutant glioma. RNA-sequencing on paired wild-type and IDH1R132H cells revealed inhibition of cholesterol biosynthesis and activation of cellular stress in IDH1R132H cells, which were reversible with a mutant IDH1 inhibitor. GSK-J4 caused further repression of cholesterol biosynthesis pathway genes through H3K27me3 deposition and exacerbated the ATF4-mediated integrated stress response. Belinostat inhibited anti-apoptotic pathways through activation of TGF-{beta} signaling and induced cell cycle arrest. Together, the GSK-J4 and Belinostat combination activated DDIT3/CHOP-dependent apoptosis in IDH1-mutant cells and extended survival in an IDH1-mutant orthotopic model in vivo. ConclusionsThese results provide a possible therapeutic approach that exploits epigenetic vulnerabilities of IDH-mutant gliomas. Key points- Combination of GSK-J4 and Belinostat selectively targets IDH1-mutant cells. - GSK-J4 downregulates cholesterol biosynthesis and activates an ATF4-mediated stress response. - Belinostat activates the TGF{beta} pathway, induces G2/M arrest and inhibits anti-apoptotic pathways. Importance of the studyIDH1/2 genes are frequently mutated in low grade glioma and secondary glioblastoma. These tumors exhibit a distinct epigenomic signature with increased DNA and histone methylation; therefore, identifying and exploiting their epigenetic vulnerabilities may lead to effective therapies. We discovered that targeting of KDM6A/6B together with HDACs provides a promising therapeutic approach for IDH1-mutant glioma.

cancer biology↗