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

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 () and Jianjun Gao ()
Additional contact information
Omar Alhalabi: The University of Texas MD Anderson Cancer Center
Jianfeng Chen: The University of Texas MD Anderson Cancer Center
Yuxue Zhang: The University of Texas MD Anderson Cancer Center
Yang Lu: The University of Texas MD Anderson Cancer Center
Qi Wang: The University of Texas MD Anderson Cancer Center
Sumankalai Ramachandran: The University of Texas MD Anderson Cancer Center
Rebecca Slack Tidwell: The University of Texas MD Anderson Cancer Center
Guangchun Han: The University of Texas MD Anderson Cancer Center
Xinmiao Yan: The University of Texas MD Anderson Cancer Center
Jieru Meng: The University of Texas MD Anderson Cancer Center
Ruiping Wang: The University of Texas MD Anderson Cancer Center
Anh G. Hoang: The University of Texas MD Anderson Cancer Center
Wei-Lien Wang: The University of Texas MD Anderson Cancer Center
Jian Song: The University of Texas MD Anderson Cancer Center
Lidia Lopez: The University of Texas MD Anderson Cancer Center
Alex Andreev-Drakhlin: The University of Texas MD Anderson Cancer Center
Arlene Siefker-Radtke: The University of Texas MD Anderson Cancer Center
Xinqiao Zhang: The University of Texas MD Anderson Cancer Center
William F. Benedict: The University of Texas MD Anderson Cancer Center
Amishi Y. Shah: The University of Texas MD Anderson Cancer Center
Jennifer Wang: The University of Texas MD Anderson Cancer Center
Pavlos Msaouel: The University of Texas MD Anderson Cancer Center
Miao Zhang: The University of Texas MD Anderson Cancer Center
Charles C. Guo: The University of Texas MD Anderson Cancer Center
Bogdan Czerniak: The University of Texas MD Anderson Cancer Center
Carmen Behrens: The University of Texas MD Anderson Cancer Center
Luisa Soto: The University of Texas MD Anderson Cancer Center
Vassiliki Papadimitrakopoulou: The University of Texas MD Anderson Cancer Center
Jeff Lewis: The University of Texas MD Anderson Cancer Center
Waree Rinsurongkawong: The University of Texas MD Anderson Cancer Center
Vadeerat Rinsurongkawong: The University of Texas MD Anderson Cancer Center
Jack Lee: The University of Texas MD Anderson Cancer Center
Jack Roth: The University of Texas MD Anderson Cancer Center
Stephen Swisher: The University of Texas MD Anderson Cancer Center
Ignacio Wistuba: The University of Texas MD Anderson Cancer Center
John Heymach: The University of Texas MD Anderson Cancer Center
Jing Wang: The University of Texas MD Anderson Cancer Center
Matthew T. Campbell: The University of Texas MD Anderson Cancer Center
Eleni Efstathiou: The University of Texas MD Anderson Cancer Center
Mark Titus: The University of Texas MD Anderson Cancer Center
Christopher J. Logothetis: The University of Texas MD Anderson Cancer Center
Thai H. Ho: Mayo Clinic
Jianjun Zhang: The University of Texas MD Anderson Cancer Center
Linghua Wang: The University of Texas MD Anderson Cancer Center
Jianjun Gao: The University of Texas MD Anderson Cancer Center

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-29397-z

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