Preclinical validation of an anti-MNK1 aptamer targeting pancreatic cancer stem cells
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, driven by late diagnosis, early metastasis, and therapy resistance. MAP kinase-interacting kinase 1 (MNK1) has been implicated in tumor progression and cancer stem cell (CSC) maintenance. Here, we present robust preclinical validation of apMNKQ2, a DNA aptamer targeting MNK1, as a therapeutic candidate against PDAC and CSCs. apMNKQ2 reduced MNK1 and anti-apoptotic proteins (MCL1, XIAP), impairing cell cycle progression in PDAC patient-derived xenograft (PDX) cell lines, and inhibited PDAC proliferation, migration, and epithelial-to-mesenchymal transition, leading to reduced lung colonization in vivo. Notably, apMNKQ2 strongly targeted PDAC CSCs, reducing CD133 and CXCR4 expression, clonogenicity and in vivo tumor initiation over 600-fold. Free apMNKQ2 (without transfection agents) entered PDAC cells efficiently, retaining anti-CSC activity. Systemic delivery of free apMNKQ2 accumulated in tumors, was well tolerated up to 400 mg/kg and showed no toxicity. Importantly, 10 mg/kg of apMNKQ2 produced strong anti-tumor effects in PDX models. Increasing the dose 20-fold enhanced tumor uptake but not efficacy, suggesting a therapeutic plateau at 10 mg/kg. These findings identify MNK1 as a key regulator of PDAC and support apMNKQ2 as a promising therapeutic, with CSC-targeting and anti-metastatic properties suited to combat this aggressive malignancy.