Frederick Wilson

Focus of Research: Cancer genomics

Currently Attending:
Harvard

View more Publications by Frederick Wilson

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

Co-Authors Kryukov GV, Wilson FH, Ruth JR, Paulk J, Tsherniak A, Marlow SE, Vazquez F, Weir BA, Fitzgerald ME, Tanaka M, Bielski CM, Scott JM, Dennis C, Cowley GS, Boehm JS, Root DE, Golub TR, Clish CB, Bradner JE, Hahn WC, Garraway LA

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.

Science 2016 Mar 11; 351 (6278): 1214-18

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