MAT2A Inhibition Blocks the Growth of MTAP-Deleted Cancer Cells by Reducing PRMT5-Dependent mRNA Splicing and Inducing DNA Damage

Cancer Cell. 2021 Feb 8;39(2):209-224.e11. doi: 10.1016/j.ccell.2020.12.010. Epub 2021 Jan 14.

Abstract

The methylthioadenosine phosphorylase (MTAP) gene is located adjacent to the cyclin-dependent kinase inhibitor 2A (CDKN2A) tumor-suppressor gene and is co-deleted with CDKN2A in approximately 15% of all cancers. This co-deletion leads to aggressive tumors with poor prognosis that lack effective, molecularly targeted therapies. The metabolic enzyme methionine adenosyltransferase 2α (MAT2A) was identified as a synthetic lethal target in MTAP-deleted cancers. We report the characterization of potent MAT2A inhibitors that substantially reduce levels of S-adenosylmethionine (SAM) and demonstrate antiproliferative activity in MTAP-deleted cancer cells and tumors. Using RNA sequencing and proteomics, we demonstrate that MAT2A inhibition is mechanistically linked to reduced protein arginine methyltransferase 5 (PRMT5) activity and splicing perturbations. We further show that DNA damage and mitotic defects ensue upon MAT2A inhibition in HCT116 MTAP-/- cells, providing a rationale for combining the MAT2A clinical candidate AG-270 with antimitotic taxanes.

Keywords: DNA damage; Fanconi anemia complex; MAT2A; PRMT5; R loops; detained introns; splicing; synergy; taxanes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase Inhibitor p16
  • DNA Damage / drug effects*
  • DNA Damage / genetics
  • Enzyme Inhibitors / pharmacology*
  • Gene Deletion
  • HCT116 Cells
  • HEK293 Cells
  • Humans
  • Methionine Adenosyltransferase / antagonists & inhibitors*
  • Methionine Adenosyltransferase / genetics
  • Mice, Inbred NOD
  • Mice, Nude
  • Mice, SCID
  • Neoplasms / drug therapy
  • Neoplasms / genetics
  • Protein-Arginine N-Methyltransferases / genetics*
  • Purine-Nucleoside Phosphorylase / genetics*
  • RNA Splicing / drug effects*
  • RNA Splicing / genetics
  • RNA, Messenger / genetics*
  • S-Adenosylmethionine / metabolism

Substances

  • Cyclin-Dependent Kinase Inhibitor p16
  • Enzyme Inhibitors
  • RNA, Messenger
  • S-Adenosylmethionine
  • PRMT5 protein, human
  • Protein-Arginine N-Methyltransferases
  • Purine-Nucleoside Phosphorylase
  • 5'-methylthioadenosine phosphorylase
  • MAT2A protein, human
  • Methionine Adenosyltransferase