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, Jianjun Gao

Journal: Nature communications 2022;13(1):1797

PMID: 35379845

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Abstract

Methylthioadenosine phosphorylase, an essential enzyme for the adenine salvage pathway, is often deficient (MTAP) 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 urothelial carcinoma (UC) with the primary endpoint of overall response rate (ORR). Three of 7 enrolled MTAP patients show response to pemetrexed (ORR 43%). Furthermore, a historic cohort shows 4 of 4 MTAP 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 associates with an improved response rate to pemetrexed. Our data demonstrate a synthetic lethal interaction between MTAP and de novo purine inhibition, which represents a promising therapeutic strategy for larger prospective trials.

Address: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.; Department of Nuclear Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.; Department of Biostatistics,, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.; Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.; Department of Thoracic, Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.; Department of Translational molecular pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.; Department of Thoracic and Cardiovascular surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.; Division of Medical Oncology, Mayo Clinic, Phoenix, AZ, USA.; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. [email protected].; The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences (GSBS), Houston, TX, USA. [email protected].; Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. [email protected].

DOI: 10.1038/s41467-022-29397-z

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MeSH Terms: Carcinoma, Transitional Cell, Folic Acid Antagonists, Humans, Prospective Studies, Retrospective Studies, Urinary Bladder Neoplasms