Abstract 7062: EP102: Pharmacological inhibition of METTL3 is effective as a monotherapy and potentiates radiation therapy in pancreatic adenocarcinoma via DNA damage and stemness modulation.

Abstract N6-methyladenosine (m6A) is the most abundant internal mRNA modification, regulating RNA stability, splicing, and translation. METTL3, the RNA methyltransferase predominantly responsible for the addition of m6A, is frequently overexpressed in solid tumors and acts as an oncogenic driver by promoting proliferation, survival, and therapy resistance. In pancreatic ductal adenocarcinoma (PDAC), METTL3 upregulation correlates with aggressive disease and poor prognosis. Mechanistic studies implicate METTL3 in PDAC progression through m6A-dependent regulation of oncogenic transcripts and pathways such as DNA damage repair, contributing to chemoresistance and tumor stemness. Radiotherapy is an established treatment modality for pancreatic cancer, used in neoadjuvant, adjuvant, and locally advanced settings, often combined with chemotherapy. The aim of this work was to evaluate EP102, a selective METTL3 inhibitor, for its efficacy and synergy with radiation therapy in PDAC xenografts and to explore underlying mechanisms. Two independent studies were conducted in Balb/c nude mice bearing PANC08.13 tumors. EP102 was administered alone (47 mg/kg PO, TIW) or combined with radiation (3 Gy × 3) in Study 1 and EP102 alone at 30 mg/kg (PO, TIW) or combined with radiation (2 Gy x 3) in Study 2. Both studies confirmed significant dose dependent tumor growth inhibition by EP102 and marked tumor shrinkage with the combination, supporting synergy across doses. Blood profiling after 4 days of treatment indicated minimal hematologic impact with EP102 alone, supporting its tolerability. Radiation alone and in combination with EP102 led to a pronounced decrease in lymphocytes; notably, the combination suggested a compensatory shift toward innate immunity, where myeloid cells may transiently expand or activate to maintain host defense under genotoxic stress. Mechanistic analysis by Western blot revealed that METTL3 inhibition impairs the expression of key DNA repair and survival genes leading to accumulation of DNA damage: γH2AX and p-CHK2 were upregulated, indicating double-strand break accumulation and checkpoint activation. Importantly, when combined with radiation, EP102 markedly amplified these effects: γH2AX and p-CHK2 surged, BRCA1 and MCL-1 were strongly downregulated, and the expression of stemness marker OV-6 dropped significantly. This combination triggered robust apoptosis and pronounced HR deficiency, correlating with dramatic tumor regression. Together, these findings support a model where EP102 impairs m6A-dependent repair and survival pathways, and radiation potentiates this disruption, driving synergistic antitumor activity. These findings validate METTL3 as a therapeutic target and provide a strong rationale for combining EP102 with radiotherapy in pancreatic cancer. Citation Format: Andrea Casazza, Nicolas Parmentier, Catherine Sorlet, Killian Oukoloff, Guillaume Dutheuil, Graeme L. Fraser. EP102: Pharmacological inhibition of METTL3 is effective as a monotherapy and potentiates radiation therapy in pancreatic adenocarcinoma via DNA damage and stemness modulation abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7062.