Published in the journal Nature Communications*, results from a first-in-human, phase I clinical trial of an oral, potent and reversible inhibitor of methionine adenosyltransferase 2 A (MT2A)—a key enzyme involved in methionine metabolism—provide preliminary evidence of clinical activity and proof-of-mechanism in patients with MTAP-deleted advanced solid tumors which had progressed on at least one prior line of treatment.
“Dysregulated cellular metabolism, a hallmark of cancer, energizes tumor cells to grow, proliferate out of control and spread to other organs. Understanding the mechanisms of altered cancer cell metabolism and identifying new therapeutic targets for blocking this accelerated tumor growth and metastasis are key to developing new treatment strategies,” said Josep Tabernero, Head of the Medical Oncology Department at the Vall d’Hebron University Hospital, VHIO’s Director, and corresponding author of this present study.
Deletions of the MTAP gene occur in approximately 15% of tumors including pancreatic ductal adenocarcinoma, non-small cell lung cancer (NSCLC), gastric cancer and glioblastoma, among others, and are associated with a poor prognosis. These tumors have been shown to be vulnerable to decreases in the concentration of S-adenosylmethionine (SAM), a molecule implicated in cell death, proliferation and differentiation.
Results from preclinical studies have demonstrated that inhibiting the MAT2A enzyme, which is primarily responsible for the synthesis of SAM, decreases the concentration of SAM leading to cancer cell death, a successful example of synthetic lethality supporting efforts to develop MAT2A inhibitors.
AG-270/S095033 is the first MAT2A inhibitor to enter clinical development. While other MAT2A inhibitors are in early clinical development, this present study is the first to report the results of single agent MAT2A blockade in patients. Forty patients with MTAP-deleted advanced solid tumors were treated with this first-in-class inhibitor, and results showed that maximal reductions in plasma SAM concentrations ranged from 54% to 70%.
“Even though our data demonstrated modest signals of anti-tumor activity, durable responses and disease stabilization were observed in some patients with a disease control rate at 16 weeks of 17.5 %. Results from this study provide preliminary evidence of clinical activity and proof-of-mechanism for MAT2A inhibition as a potential new treatment strategy for patients with MTAP-deleted cancer,” said Elena Garralda, a Medical Oncologist at Vall d’Hebron, Director of VHIO’s Research Unit for Molecular Therapy of Cancer (UITM)-CaixaResearch, and a co-author of the study.
While MAT2A inhibition appears to be promising, results from this study indicated a high rate of resistance and clinical benefit was short-term. More investigations are therefore warranted to unravel the full potential of MAT2A as a therapeutic target.
“Our data support future investigations testing combinations of MAT2 inhibitors with other therapies targeting tumor cell proliferation, or with second generation MAT2 inhibitors already in clinical development,” concluded Tabernero.
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Reference
Gounder M, Johnson M, Heist RS, Shapiro GI, Postel-Vinay S, Wilson FH, Garralda E, Wulf G, Almon C, Nabhan S, Aguado-Fraile E, He P, Romagnoli M, Hossain M, Narayanaswamy R, Sadou-Dubourgnoux A, Cooper M, Askoxylakis V, Burris HA, Tabernero J. MAT2A inhibitor AG-270/S095033 in patients with advanced malignancies: a phase I trial. Nat Commun. 2025 Jan 6;16(1):423.
