RRC ID 77048
Author Kalev P, Hyer ML, Gross S, Konteatis Z, Chen CC, Fletcher M, Lein M, Aguado-Fraile E, Frank V, Barnett A, Mandley E, Goldford J, Chen Y, Sellers K, Hayes S, Lizotte K, Quang P, Tuncay Y, Clasquin M, Peters R, Weier J, Simone E, Murtie J, Liu W, Nagaraja R, Dang L, Sui Z, Biller SA, Travins J, Marks KM, Marjon K.
Title MAT2A Inhibition Blocks the Growth of MTAP-Deleted Cancer Cells by Reducing PRMT5-Dependent mRNA Splicing and Inducing DNA Damage.
Journal Cancer Cell
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.
Volume 39(2)
Pages 209-224.e11
Published 2021-2-8
DOI 10.1016/j.ccell.2020.12.010
PII S1535-6108(20)30658-9
PMID 33450196
MeSH 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
IF 26.602
Human and Animal Cells KP4(RCB1005)