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

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

Peter Kalev  1 , Marc L Hyer  2 , Stefan Gross  3 , Zenon Konteatis  4 , Chi-Chao Chen  5 , Mark Fletcher  5 , Max Lein  6 , Elia Aguado-Fraile  7 , Victoria Frank  1 , Amelia Barnett  1 , Everton Mandley  2 , Joshua Goldford  8 , Yue Chen  6 , Katie Sellers  8 , Sebastian Hayes  8 , Kate Lizotte  8 , Phong Quang  1 , Yesim Tuncay  1 , Michelle Clasquin  8 , Rachel Peters  9 , Jaclyn Weier  1 , Eric Simone  10 , Joshua Murtie  11 , Wei Liu  5 , Raj Nagaraja  6 , Lenny Dang  3 , Zhihua Sui  4 , Scott A Biller  4 , Jeremy Travins  4 , Kevin M Marks  1 , Katya Marjon  12
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Free article

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

Peter Kalev et al. Cancer Cell. .
Free article

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.

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Conflict of interest statement

Declaration of interests The authors are current or past employees and shareholders of Agios Pharmaceuticals, Inc. PCT/US2020/018036 by Agios Pharmaceuticals, Inc.: Hyer, M.L., Kalev, P., Marjon, K., Marks, K. Combination therapies for use in treating cancer.

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