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 (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.

• Authors: Omar Alhalabi, Jianfeng Chen, Yuxue Zhang, Yang Lu, Qi Wang, Sumankalai Ramachandran, Rebecca Slack Tidwell, Guangchun Han, Xinmiao Yan, Jieru Meng, Ruiping Wang, Anh G Hoang, Wei-Lien Wang, Jian Song, Lidia Lopez, Alex Andreev-Drakhlin, Arlene Siefker-Radtke, Xinqiao Zhang, William F Benedict, Amishi Y Shah, Jennifer Wang, Pavlos Msaouel, Miao Zhang, Charles C Guo, Bogdan Czerniak, Carmen Behrens, Luisa Soto, Vassiliki Papadimitrakopoulou, Jeff Lewis, Waree Rinsurongkawong, Vadeerat Rinsurongkawong, Jack Lee, Jack Roth, Stephen Swisher, Ignacio Wistuba, John Heymach, Jing Wang, Matthew T Campbell, Eleni Efstathiou, Mark Titus, Christopher J Logothetis, Thai H Ho, Jianjun Zhang, Linghua Wang, Jianjun Gao
• Journal: Nature communications (Nat Commun) Vol. 13 Issue 1 Pg. 1797 (04 04 2022) ISSN: 2041-1723 [Electronic] England
• PMID: 35379845 (Publication Type: Clinical Trial, Phase II, Journal Article)
• Copyright: © 2022. The Author(s).

Chemical References

• Folic Acid Antagonists

Topics

• Carcinoma, Transitional Cell
• Folic Acid Antagonists (pharmacology, therapeutic use)
• Humans
• Prospective Studies
• Retrospective Studies
• Urinary Bladder Neoplasms