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• W2767186836 abstract "An understanding of driver genetic events in tumorigenesis has led to the development of targeted therapies with clinical benefit for subsets of patients with melanoma, non-small cell lung cancer, and other malignancies. The identification of new cancer vulnerabilities may provide additional therapeutic opportunities for malignancies refractory to standard treatments and may expand the use of targeted therapies to a broader patient population. To identify new cancer vulnerabilities and associated genetic features, we have integrated insights about recurrent genetic alterations (from the Cancer Cell Line Encyclopedia) with cancer cell line dependencies identified from genome-scale RNA interference (from Project Achilles). Using this approach, we find that cancer cell lines harboring a highly-recurrent alteration (homozygous deletion of the gene encoding methylthioadenosine phosphorylase or MTAP) show selective dependence on protein arginine methyltransferase 5 (PRMT5) and its binding partner WDR77, core components of the methylosome. Homozygous loss of MTAP occurs as a passenger event in cancer due to its proximity to the commonly-deleted tumor suppressor gene CDKN2A. MTAP is lost in >40% of glioblastomas and in 25-30% of melanomas, urothelial carcinomas, and pancreatic adenocarcinomas (in addition to other cancers). MTAP cleaves methylthioadenosine (MTA) to generate precursor substrates for methionine and adenine salvage pathways, which are compromised with MTAP loss. While MTAP deletion in cancer has long been recognized as a potential vulnerability (as tumors with MTAP loss are dependent on de novo purine synthesis), therapeutic strategies to exploit MTAP loss have not been successfully implemented. Our findings credential PRMT5 as a previously-unrecognized potential therapeutic target in MTAP-deleted cancers. We have performed mechanistic studies to confirm a role for MTAP in modulating sensitivity to genetic depletion of PRMT5 or WDR77. Furthermore, we propose a mechanism by which homozygous MTAP deletion confers a selective dependency on PRMT5 and WDR77. We show that loss of MTAP leads to increased intracellular levels of MTA, which in turn specifically inhibits the catalytic activity of PRMT5. Since PRMT5 activity is essential for cell viability, MTAP-deleted cells may have some degree of basal inhibition of PRMT5 activity that confers heightened sensitivity to further reduction in PRMT5 activity with gene depletion. Given the frequency of homozygous MTAP loss in cancer, our findings suggest a potential role for PRMT5 inhibition in multiple malignancies, either as a single agent or possibly in combination with other therapies. As MTAP loss is not mutually exclusive of oncogenic drivers in cancer (such as activating BRAF mutations in melanoma or EGFR mutations in lung cancer), it may theoretically be possible to combine PRMT5 inhibition with targeting of oncogenic drivers in an effort to augment anti-tumor activity and possibly delay or prevent the emergence of drug resistance. Citation Format: Frederick H. Wilson. PRMT5 as a therapeutic target in MTAP-deleted cancers [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr IA24." @default.
• W2767186836 created "2017-11-10" @default.
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• W2767186836 date "2017-10-01" @default.
• W2767186836 modified "2023-09-27" @default.
• W2767186836 title "Abstract IA24: PRMT5 as a therapeutic target inMTAP-deleted cancers" @default.
• W2767186836 doi "https://doi.org/10.1158/1538-8514.synthleth-ia24" @default.
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