# In Vitro Evaluation of Electrochemotherapy Combined with Sotorasib in Pancreatic Carcinoma Cell Lines Harboring Distinct KRAS Mutations

## TL;DR

This study explores combining electrochemotherapy with sotorasib to treat pancreatic cancer cells with different KRAS mutations, showing promising additive effects in some cell lines.

## Contribution

The study is the first to investigate the combination of electrochemotherapy and sotorasib in pancreatic cancer cell lines with distinct KRAS mutations.

## Key findings

- ECT alone significantly reduced cell viability, especially in KRAS G12C-mutated MIA PaCa-2 cells.
- Combining ECT with sotorasib showed an additive effect in MIA PaCa-2 cells but no synergy was observed.
- The results suggest potential for combining physical and molecular therapies in pancreatic cancer treatment.

## Abstract

Pancreatic cancer is among the deadliest malignancies, with limited treatment options and poor prognosis. Novel strategies are therefore urgently needed. Sotorasib, a KRAS G12C-specific inhibitor, offers targeted treatment for a small subset of patients with this mutation. Electrochemotherapy (ECT), which enhances the cytotoxicity of chemotherapeutic agents through electroporation-induced membrane permeabilization, has shown promise in various tumor types, including deep-seated malignancies such as pancreatic cancer. Combining ECT with sotorasib may potentiate antitumor effects in KRAS G12C-mutated pancreatic cancer; however, preclinical data on such combinations are lacking. This proof-of-concept study evaluated the cytotoxic effects of ECT using bleomycin (BLM) or cisplatin (CDDP) in combination with sotorasib in KRAS G12C-mutated MIA PaCa-2 and KRAS G12D-mutated PANC-1 pancreatic cancer cell lines. ECT alone significantly reduced cell viability, particularly in MIA PaCa-2 cells, where electric pulses induced approximately 75% cell death. Combining ECT with sotorasib resulted in an additive effect on KRAS G12C-mutated MIA PaCa-2 cells, though no synergy was observed, likely due to the high intrinsic sensitivity to electric pulses. These results support the potential of combining physical and molecular therapies in a subset of pancreatic cancer patients and lay the groundwork for further in vivo studies to optimize treatment parameters and explore clinical translatability.