Developing a Multimodal miR-15a Mimic to Overcome Gemcitabine and RAS(ON) Inhibitor Daraxonrasib Resistance in Pancreatic Ductal Adenocarcinoma

MTX-5-FU-Gem-miR-15a shows low-nanomolar potency in five pancreatic ductal adenocarcinoma cell lines and suppresses metastatic tumor growth in vivo at 4 mg/kg.

• Why it matters: Acquired resistance to gemcitabine and the RAS(ON) inhibitor daraxonrasib limits durable responses in metastatic PDAC, creating a need for therapies that retain activity in resistant settings.
• What they did: The authors chemically modified tumor-suppressive miR-15a with methotrexate, 5-fluorouracil, and gemcitabine, then tested potency in resistant models, profiled transcriptomes/proteomes, and evaluated synergy with daraxonrasib (mean Bliss 22.52) plus STING-TBK1 activation.
• The result: Treatment induced S-phase accumulation, DNA damage, apoptosis, checkpoint/survival protein suppression, partial remodeling of gemcitabine resistance (including restored dCK and reduced ABCC1/ABCC3), and increased IFN-β and CXCL10 secretion, while remaining potent in three patient-derived organoids.

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