Abstract B071: Preclinical Evaluation of Tumor Treating Fields (TTFields) Applied with KRAS Inhibitors in Pancreatic Ductal Adenocarcinoma Models

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains among the most lethal malignancies, with limited survival despite advances in systemic therapy. Activating KRAS mutations, present in approximately 90% of PDACs, contribute to tumor progression in part through regulation of c-Myc. Tumor Treating Fields (TTFields) therapy has recently been approved together with gemcitabine and nab-paclitaxel (Gem/NabP) for unresectable locally advanced PDAC, and preclinical findings indicate that TTFields suppress c-Myc expression. This study investigated whether applying TTFields alongside KRAS inhibition enhances antitumor activity in PDAC models. KRAS G12D-mutant mouse KPC and human Panc1 cells were exposed for 72 h to TTFields (150 kHz; 1 or 1.62 V/cm RMS, respectively) together with increasing concentrations of the pan-KRAS inhibitor daraxonrasib or the KRAS G12D-selective inhibitor zoldonrasib. Cell number and apoptosis were quantified by FACS analysis, while c-Myc expression was evaluated by Western blotting. Additional in vitro experiments assessed TTFields applied with daraxonrasib and Gem/NabP. KRAS inhibition reduced cell viability in a dose-dependent manner and increased apoptosis, effects that were further enhanced by concurrent TTFields application. The greatest reduction in cell number was observed when TTFields, daraxonrasib, and Gem/NabP were applied together compared with either single-modality or dual-modality treatment. Both TTFields and daraxonrasib downregulated c-Myc protein expression, with a stronger reduction following concurrent treatment. In vivo, orthotopic KPC tumors were established in male C57BL/6 mice before treatment with TTFields or sham heat for 9 days, with daraxonrasib (10 mg/kg) administered orally on treatment days 3 and 6. At the applied concentration, daraxonrasib alone produced only a modest effect. Applying TTFields together with daraxonrasib resulted in tumor growth inhibition relative to control and to treatment with daraxonrasib alone. These findings demonstrate that concurrent application of TTFields and daraxonrasib enhances antitumor activity in KRAS G12D PDAC models in vitro and in vivo, potentially through modulation of c-Myc. In addition, application of TTFields with daraxonrasib on the Gem/NabP backbone may provide further benefit.