Journal
CANCER CELL
Volume 39, Issue 2, Pages 209-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2020.12.010
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Funding
- Agios Pharmaceuticals, Inc.
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In MTAP-deleted cancers, potent MAT2A inhibitors were found to reduce SAM levels and decrease PRMT5 activity, leading to transcriptional perturbations that cause DNA damage and mitotic defects. This provides a rationale for combining MAT2A inhibitors with anti-mitotic drugs for treatment.
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 2 alpha (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.
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