MAT2A (methionine adenosyltransferase 2 alpha) is a critical enzyme within the methionine salvage pathway responsible for generating the universal methyl group donor, S-adenosyl methionine (SAM). We have developed a first-in-class small molecule inhibitor of MAT2A, AG-270, currently in a phase 1 clinical study (ClinicalTrials.gov NCT03435250) for the treatment of patients with solid tumors or lymphomas with MTAP (methylthioadenosine phosphorylase) deletion. The MTAP gene is deleted in approximately 15% of all human cancers, including non-small cell lung cancer (NSCLC; ~15-25%), pancreatic (~25%) and esophageal (~30%) cancer, and glioblastoma (~50%). To prioritize candidate combination partners for AG-270, a cell-based in vitro screening approach was employed using MTAP-null cell lines, in which AG-270 was combined with standard-of-care (SOC) agents as well as agents targeting pathways with hypothesized mechanistic links to MAT2A. Some of the best performing enhancers from this screen included paclitaxel (and docetaxel, using orthogonal screens) and gemcitabine. To assess the robustness of these combination findings in clinically relevant in vivo models, a series of patient-derived xenograft (PDX) experiments was undertaken to evaluate tolerability and efficacy in mice. Results demonstrated that AG-270, when combined with taxanes (paclitaxel/docetaxel) or gemcitabine, was well tolerated using SOC plasma exposures less than or equal to those achieved in patients. Importantly, combining AG-270 with taxanes and gemcitabine yielded additive-to-synergistic anti-tumor activity, with the docetaxel combination yielding 50% complete tumor regressions (CRs) in 2-3 PDX models. To study the mechanism of action, MAT2A was inhibited in vitro within HCT-116 MTAP −/− and wild-type cells, and we observed RNA splicing changes (via detained introns) altering genes involved in cell cycle regulation and DNA damage response, with a more pronounced effect found in the MTAP −/− genetic setting. Moreover, detained introns involving these same two pathways were modulated in MTAP −/− NSCLC PDX models treated with AG-270. Taken together, these data suggest AG-270 complements the known mechanism of action of taxanes and gemcitabine, and leads to enhanced DNA damage and inhibition of cellular proliferation. This work has helped identify a therapeutic strategy of combining AG-270 with taxanes and gemcitabine, which is currently being explored in an ongoing phase 1 clinical trial (NCT03435250).
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Citation Format: Marc L. Hyer, Peter Kalev, Mark Fletcher, Chi-Chao Chen, Elia Aguado-Fraile, Everton Mandley, Sheila Newhouse, Max Lein, Raj Nagaraja, Yesim Tuncay, Josh Murtie, Kevin M. Marks, Katya Marjon. The MAT2A inhibitor, AG-270, combines with both taxanes and gemcitabine to yield enhanced anti-tumor activity in patient-derived xenograft models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3090.