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

Science. 2016 Mar 11;351(6278):1214-8. doi: 10.1126/science.aad5214. Epub 2016 Feb 11.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Deoxyadenosines / metabolism
  • Deoxyadenosines / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Gene Deletion
  • Humans
  • Isoquinolines / pharmacology
  • Neoplasms / drug therapy*
  • Neoplasms / enzymology
  • Protein-Arginine N-Methyltransferases / antagonists & inhibitors
  • Protein-Arginine N-Methyltransferases / genetics
  • Protein-Arginine N-Methyltransferases / metabolism*
  • Purine-Nucleoside Phosphorylase / genetics
  • Purine-Nucleoside Phosphorylase / metabolism*
  • Pyrimidines / pharmacology
  • Thionucleosides / metabolism
  • Thionucleosides / pharmacology
  • Transcription Factors

Substances

  • Deoxyadenosines
  • Enzyme Inhibitors
  • GSK3235025
  • Isoquinolines
  • Pyrimidines
  • Thionucleosides
  • Transcription Factors
  • WDR77 protein, human
  • 5'-methylthioadenosine
  • PRMT5 protein, human
  • Protein-Arginine N-Methyltransferases
  • Purine-Nucleoside Phosphorylase
  • 5'-methylthioadenosine phosphorylase