Abstract IA24: PRMT5 as a therapeutic target in MTAP-deleted cancers

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 ...
Source: Molecular Cancer Therapeutics - Category: Cancer & Oncology Authors: Tags: Resistance against Drug Combinations: Oral Presentations - Invited Abstracts Source Type: research