S2632
Radiobiology - Tumour radiobiology
ESTRO 2026
IGF1 axis represents a previously unrecognized driver of ACC progression distinct from PDAC biology. These findings demonstrate that epitranscriptomic regulation through METTL3 plays a central role in ACC pathogenesis and therapeutic resistance, providing rationale for RNA methylation inhibitor-based therapeutic strategies combined with radiation therapy for this rare and treatment-refractory malignancy.
Group, Research Institute G.K., Tokyo, Japan. 5 Biological Data Science Research Group, Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology, Tokyo, Japan. 6 Department of Gastroenterological Surgery, The University of Osaka Graduate School of Medicine, Osaka, Japan Purpose/Objective: Pancreatic acinar cell carcinoma (ACC) is a rare malignancy accounting for less than 1% of pancreatic cancers with distinct molecular characteristics from pancreatic ductal adenocarcinoma (PDAC). Unlike PDAC, ACC harbors few KRAS mutations and also exhibits lower frequencies of TP53 and CDKN2A mutations compared to PDAC, yet demonstrates marked resistance to conventional therapies 1. We previously reported that the RNA methyltransferase METTL3 contributes to therapeutic resistance in PDAC through PLK1 regulation 2,3. This study aimed to elucidate the pathogenic mechanisms of ACC and identify novel therapeutic targets using a genetically engineered mouse model. Material/Methods: We generated double-transgenic mice (WTg) by crossing EL1-TAg mice with CAG-M3 mice to induce ACC with METTL3 overexpression. ACC tumors were analyzed by methylated RNA immunoprecipitation sequencing (MeRIP-seq) and single-cell RNA sequencing (scRNA-seq) to identify METTL3-mediated molecular mechanisms. Therapeutic resistance was evaluated using the mouse ACC cell line 266-6 with PRSS1 knockdown in co-culture systems with the fibroblast cell line 3T3. Results: WTg mice developed aggressive ACC with significantly larger tumors and shortened survival compared to controls. MeRIP-seq identified METTL3-mediated methylation of genes regulating cell cycle progression, similar to patterns observed in PDAC. scRNA-seq analysis revealed METTL3-PRSS1-F2R-IGF1 signaling axis. METTL3 regulates PRSS1 expression through m6A modification of its 3'UTR, tumor-secreted PRSS1 activates inflammatory CAFs (iCAFs) via F2R receptor, and iCAFs reciprocally secrete insulin-like growth factor 1 (IGF1) to promote ACC growth. This signaling cascade maintains cancer stem cell properties and confers resistance to chemotherapy and radiation. PRSS1 knockdown enhanced sensitivity to cisplatin, 5- fluorouracil, and ionizing radiation specifically in CAF co-culture conditions. Treatment with the selective METTL3 inhibitor STM2457 4 produced marked tumor regression and synergized with FOLFIRINOX chemotherapy and radiation. Conclusion: This study elucidates critical pathogenic mechanisms unique to ACC pathogenesis. The METTL3-PRSS1-F2R-
References: 1. Florou, V. et al. Comparative Genomic Analysis of Pancreatic Acinar Cell Carcinoma (PACC) and Pancreatic Ductal Adenocarcinoma (PDAC) Unveils New Actionable Genomic Aberrations in PACC. Clin Cancer Res29, 3408-3417 (2023).2. Taketo, K. et al. The epitranscriptome m6A writer METTL3 promotes chemo- and radioresistance in pancreatic cancer cells. International journal of oncology52, 621-629 (2018).3. Tatekawa, S. et al. N(6)-methyladenosine methylation- regulated polo-like kinase 1 cell cycle homeostasis as a potential target of radiotherapy in pancreatic adenocarcinoma. Scientific reports12, 11074 (2022).4. Yankova, E. et al. Small-molecule inhibition of METTL3 as a strategy against myeloid leukaemia. Nature593, 597-601 (2021). Keywords: METTL3, RNA methylation, Acinar cell carcinoma Digital Poster 2202 Ro 90-7501 impairs DNA double-strand break repair and enhances radiosensitivity in breast and bladder cancer cells Charbel Joseph Feghaly 1 , Hanine Bou Hadir 1 , Sima Hussayni 2 , Elie Estephan 1 , Zahraa Kabalan 1 , Rawaa Al Bakir 1 , Habib Rammal 2 , Joey Abou Chaaya 1 , Rafka Challita 2 , Rana El Hassan 2 , Larry Bodgi 1,2
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