Targeting MTHFD2 to Exploit Cancer-Specific Metabolism and the DNA Damage Response.

Alanna C Green, Martin Henriksson, Thomas Helleday, Louise Ramos

Journal: Cancer research 2024;84(1):9-16

PMID: 37922465

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Abstract

The one-carbon folate enzyme methylenetetrahydrofolate dehydrogenase/cyclohydrolase 2 (MTHFD2) is a promising therapeutic target in cancer. MTHFD2 is upregulated across numerous cancer types, promotes growth and metastasis of cancer, and correlates with poorer survival. Recent studies have developed small-molecule inhibitors to the isozymes MTHFD2 and MTHFD1 that show promise as anticancer agents through different mechanisms. This review discusses the current understanding of the function of MTHFD2 in cancer and the status of inhibitors for treating MTHFD2-overexpressing cancers.

Address: Weston Park Cancer Centre and Division of Clinical Medicine, School of Medicine and Population Health, Faculty of Health, University of Sheffield, Sheffield, United Kingdom.; Vancouver Prostate Centre and Department of Experimental Medicine, University of British Columbia, Vancouver, British Columbia, Canada.; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.; Weston Park Cancer Centre and Division of Clinical Medicine, School of Medicine and Population Health, Faculty of Health, University of Sheffield, Sheffield, United Kingdom.; Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.; Weston Park Cancer Centre and Division of Clinical Medicine, School of Medicine and Population Health, Faculty of Health, University of Sheffield, Sheffield, United Kingdom.; Mellanby Centre for Bone Research, University of Sheffield Medical School, University of Sheffield, Sheffield, United Kingdom.

DOI: 10.1158/0008-5472.CAN-23-1290