We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
MTAP deficiency creates an exploitable target for antifolate therapy in 9p21-loss cancers.
- Authors
Alhalabi, Omar; Chen, Jianfeng; Zhang, Yuxue; Lu, Yang; Wang, Qi; Ramachandran, Sumankalai; Tidwell, Rebecca Slack; Han, Guangchun; Yan, Xinmiao; Meng, Jieru; Wang, Ruiping; Hoang, Anh G.; Wang, Wei-Lien; Song, Jian; Lopez, Lidia; Andreev-Drakhlin, Alex; Siefker-Radtke, Arlene; Zhang, Xinqiao; Benedict, William F.; Shah, Amishi Y.
- Abstract
Methylthioadenosine phosphorylase, an essential enzyme for the adenine salvage pathway, is often deficient (MTAPdef) 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 MTAPdef urothelial carcinoma (UC) with the primary endpoint of overall response rate (ORR). Three of 7 enrolled MTAPdef patients show response to pemetrexed (ORR 43%). Furthermore, a historic cohort shows 4 of 4 MTAPdef 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 by inducing DNA damage, and distorting nucleotide pools. In addition, MTAP-knockdown increases sensitivity to pemetrexed. Furthermore, in a lung adenocarcinoma retrospective cohort (N = 72) from the published BATTLE2 clinical trial (NCT01248247), MTAPdef associates with an improved response rate to pemetrexed. Our data demonstrate a synthetic lethal interaction between MTAPdef and de novo purine inhibition, which represents a promising therapeutic strategy for larger prospective trials. The deficiency of MTAP, an enzyme of the adenine salvage pathway, occurs in some cancers. Here the authors perform a small cohort phase II clinical trial with metastatic MTAP-deficient urothelial cancer (UC) and show an increased overall response when comparing to MTAP-proficient UC patients.
- Subjects
PEMETREXED; TRANSITIONAL cell carcinoma; CANCER treatment; DNA damage; ADENINE; FOLIC acid
- Publication
Nature Communications, 2022, Vol 13, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-022-29397-z