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

Cancer Cell

Fecha de publicación: 8 de febrero de 2021

DOI: https://doi.org/10.1016/j.ccell.2020.12.010

Autores: Peter Kalev , Marc L. Hyer , Stefan Gross, Zenon Konteatis, Chi-Chao Chen, Mark Fletcher, Max Lein, Elia Aguado-Fraile, Victoria Frank, Amelia Barnett, Everton Mandley, Joshua Goldford, Yue Chen, Katie Sellers , Sebastian Hayes, Kate Lizotte, Phong Quang, Yesim Tuncay, Michelle Clasquin, Rachel Peters, Jaclyn Weier, Eric Simone, Joshua Murtie, Wei Liu, Raj Nagaraja, Lenny Dang,Zhihua Sui, Scott A. Biller, Jeremy Travins , Kevin M. Marks, Katya Marjon 

Background: 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.