MTAP deficiency creates an exploitable target for antifolate therapy in 9p21-loss cancers.

ABSTRACT: Methylthioadenosine phosphorylase, an essential enzyme for the adenine salvage pathway, is often deficient (MTAP^def) in tumors with 9p21 loss and hypothetically renders tumors susceptible to synthetic lethality by antifolates targeting de novo purine synthesis. Here we report our single arm phase II trial (NCT02693717) that assesses pemetrexed in MTAP^def urothelial carcinoma (UC) with the primary endpoint of overall response rate (ORR). Three of 7 enrolled MTAP^def patients show response to pemetrexed (ORR 43%). Furthermore, a historic cohort shows 4 of 4 MTAP^def patients respond to pemetrexed as compared to 1 of 10 MTAP-proficient patients. In vitro and in vivo preclinical data using UC cell lines demonstrate increased sensitivity to pemetrexed b

SUBMITTER: Alhalabi O 

PROVIDER: S-EPMC8980015 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature