MTAP deficiency creates an exploitable target for antifolate therapy in 9p21-loss cancers
Omar Alhalabi, Jianfeng Chen, Yuxue Zhang, Yang Lü, Qi Wang, Sumankalai Ramachandran, Rebecca S. Tidwell, Guangchun Han, Xinmiao Yan, Jieru Meng, Ruiping Wang, Anh Hoang, Wei‐Lien Wang, Jian H. Song, Lidia López, Alex Andreev-Drakhlin, Arlene O. Siefker‐Radtke, Xinqiao Zhang, William F. Benedict, Amishi Y. Shah, Jennifer Wang, Pavlos Msaouel, Miao Zhang, Charles C. Guo, Bogdan Czerniak, Carmen Behrens, Luisa M. Solis Soto, Vassiliki A. Papadimitrakopoulou, Jeff Lewis, Waree Rinsurongkawong, Vadeerat Rinsurongkawong, J. Jack Lee, Jack A. Roth, Stephen G. Swisher, Ignacio I. Wistuba, John V. Heymach, Jing Wang, Matthew T. Campbell, Eleni Efstathiou, Mark Titus, Christopher J. Logothetis, Thai H. Ho, Jianjun Zhang, Linghua Wang, Jianjun Gao
Abstract
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 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), MTAP def associates with an improved response rate to pemetrexed. Our data demonstrate a synthetic lethal interaction between MTAP def and de novo purine inhibition, which represents a promising therapeutic strategy for larger prospective trials.