Treatment of pancreatic cancer cells with Tumor Treating Fields (TTFields) and KRAS inhibitors

Background: Pancreatic ductal adenocarcinoma (PDAC) remains a major cause of cancer-related mortality, with limited survival despite intensive chemotherapy regimens such as FOLFIRINOX or gemcitabine/nab-paclitaxel. KRAS mutations, present in approximately 90% of PDAC cases, are a central driver of tumor aggressiveness and therapeutic resistance, in part by activating and stabilizing (and often overexpressing) c‑MYC-a key regulator of cell growth and metabolism. Tumor Treating Fields (TTFields), electric fields that disrupt cellular processes crucial for cancer cell viability, have recently been shown to suppress c-Myc at the transcript and protein levels in various cell lines. TTFields therapy was shown to improve survival in pancreatic cancer patients when used together with gemcitabine/nab-paclitaxel. The current study aims to examine the benefit of adding TTFields to KRAS inhibitors (KRASi) in PDAC preclinical models. Methods: KPC pancreatic cancer cells harboring the KRAS G12D mutation were treated for 72 hours with TTFields (150 kHz, 1 V/cm RMS) using the inovitro system. The pan-KRAS inhibitor daraxonrasib (RMC-6236) was applied at varying concentrations, either alone or in combination with TTFields. Following treatment, cell count, colony formation, and apoptosis were quantified, and an overall effect score was derived from changes in cell count and colony formation. Expression of c-Myc was assessed by real-time PCR and Western blot analysis. Results: Treatment of KPC cells with either TTFields or the KRAS inhibitor resulted in a dose-dependent reduction in cell viability and colony formation, along with increased apoptosis. The co-application of TTFields with RMC-6236 amplified these outcomes, demonstrating a synergistic interaction between the two modalities. Both TTFields and RMC-6236 independently reduced c-Myc expression, with a more pronounced downregulation observed upon co-treatment. Conclusions: Concomitant application of TTFields and the pan-KRAS inhibitor in KRAS G12D pancreatic cancer cells produced a synergistic antitumor effect, potentially mediated by modulation of the master regulator c-Myc. Ongoing studies are exploring KRAS mutation-specific inhibitors, expanding the analysis to additional pancreatic cancer cell lines harboring diverse KRAS variants, and testing the in vivo efficacy of TTFields with KRAS inhibition.