MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells.

Science
Authors
Keywords
Abstract

The discovery of cancer dependencies has the potential to inform therapeutic strategies and to identify putative drug targets. Integrating data from comprehensive genomic profiling of cancer cell lines and from functional characterization of cancer cell dependencies, we discovered that loss of the enzyme methylthioadenosine phosphorylase (MTAP) confers a selective dependence on protein arginine methyltransferase 5 (PRMT5) and its binding partner WDR77. MTAP is frequently lost due to its proximity to the commonly deleted tumor suppressor gene, CDKN2A. We observed increased intracellular concentrations of methylthioadenosine (MTA, the metabolite cleaved by MTAP) in cells harboring MTAP deletions. Furthermore, MTA specifically inhibited PRMT5 enzymatic activity. Administration of either MTA or a small-molecule PRMT5 inhibitor showed a modest preferential impairment of cell viability for MTAP-null cancer cell lines compared with isogenic MTAP-expressing counterparts. Together, our findings reveal PRMT5 as a potential vulnerability across multiple cancer lineages augmented by a common "passenger" genomic alteration.

Year of Publication
2016
Journal
Science
Volume
351
Issue
6278
Pages
1214-8
Date Published
2016 Mar 11
ISSN
1095-9203
URL
DOI
10.1126/science.aad5214
PubMed ID
26912360
PubMed Central ID
PMC4997612
Links
Grant list
KL2 TR001100 / TR / NCATS NIH HHS / United States
P01 CA163222 / CA / NCI NIH HHS / United States
U01 CA176058 / CA / NCI NIH HHS / United States
U54 CA112962 / CA / NCI NIH HHS / United States