Abstract 5714: EP102: pharmacological inhibition of METTL3 in tumor growth inhibition and comparative efficacy in combination with anti-PD1 or PARP inhibitors

Abstract METTL3 is the RNA methyltransferase predominantly responsible for the addition of N-6-methyladenosine (m6A), the most abundant epigenetic modification to mRNA. The prevalence of m6A and the activity and expression of METTL3 have been linked to the appearance and progression of numerous hematological and solid tumor cancers. EPICS has previously presented tumor growth inhibition with its small molecule inhibitors of METTL3 (“M3i”) in various models including in SKOV3 (ovarian) in NSG mice. The aim of the current study is to evaluate whether the efficacy of M3i combines favorably with anti-PD1 inhibitors in comparison to PARP inhibitors. M3i compound potency was evaluated in vitro by measuring the anti-proliferative effects in cell viability assays following a 72h treatment of A20 (B-cell lymphoma, IC50 = 310 nM), SKOV3 (ovarian, IC50 = 9 nM) and MDA-MB-231 (TNBC, IC50 = 24 nM) cells. Compound M3i-A (30 mg/kg, IP, QD) effectively elicited tumor growth inhibition (“TGI”) in SKOV3 (orthotopic implant, NSG mice) but not in A20 (syngeneic mice) either as a standalone therapy nor in combination with anti-PD1. In CD34+ humanized mice, compound M3i-B (20 mg/kg, PO, QD) elicited TGI >60% in the SKOV3 model (SC implant) and >40% TGI in the MDA-MB-231 model (orthotopic implant), but in the latter model with no additional benefit in combination with anti-PD1. SKOV3 is an HR-proficient tumor known to be less sensitive to PARP inhibitors; in a final study, M3i-B effectively prolonged survival in the SKOV3 model in NSG mice (orthotopic implant) and further demonstrated heightened efficacy when tested in combination with Olaparib (50 mg/kg, PO, QD) in data complemented by the resolution of various downstream biomarkers. The current results extend the application of METTL3 inhibitors as a single-agent in the treatment of selected tumors and further suggest that METTL3 inhibitors may be ideally combined with cancer therapies targeting DNA damage response mechanisms, such as PARP inhibitors, as a refined strategy for treatment of solid tumors. Citation Format: Graeme L. Fraser, Catherine Sorlet, Nicolas Parmentier, Killian Oukoloff, Guillaume Dutheuil. EP102: pharmacological inhibition of METTL3 in tumor growth inhibition and comparative efficacy in combination with anti-PD1 or PARP inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5714.