Effects of tumor treating fields (TTFields) with FOLFIRINOX on BRCA WT pancreatic cancer cells.

753 Background: Pancreatic cancer remains one of the most aggressive malignancies, frequently diagnosed at the locally advanced or metastatic stage. In the advanced setting, first-line chemotherapy options include gemcitabine with nab-paclitaxel or FOLFIRINOX, a combination regimen of fluorouracil, oxaliplatin, irinotecan and leucovorin. The FOLFIRINOX regimen is however associated with greater toxicity and is hence used only in patients with good performance status. BRCA-mutated tumors seem to be more sensitive to FOLFIRINOX due to the DNA-damaging, platinum-based component of this treatment regimen. Tumor Treating Fields (TTFields) are electric fields that disrupt cellular processes crucial for cancer cell viability that have shown efficacy in preclinical pancreatic cancer models; and, in various cancer types, have been shown to reduce expression of proteins from the BRCA-dependent DNA repair pathway. The current study examined the potential use of TTFields for sensitization of BRCA wild-type pancreatic cancer cells to treatment with FOLFIRINOX. Methods: Human pancreatic BRCA wild-type cancer cells BxPC3 and AsPC1 were treated with TTFields (150 kHz; 0.7 and 1 V/cm RMS, respectively), using the inovitro device. FOLFIRINOX was administered to the cells at increasing concentrations, with or without co-treatment with TTFields. After 72h of treatment, cell count, colony formation, and apoptosis were measured. For mechanistical insight, gene and protein expression were evaluated following 24, 48, or 72h of TTFields treatment. Results: TTFields application to the pancreatic cells together with FOLFIRINOX elevated the cytotoxic, clonogenic and apoptotic effects induced by FOLFIRINOX or TTFields alone. RNA sequencing data revealed that TTFields downregulated DNA damage repair, DNA replication, and cell cycle related processes. Specifically, real-time PCR and Western blot analysis demonstrated reduced expression of several central players in the BRCA DNA damage repair pathway. Conclusions: TTFields application together with FOLFIRINOX in pancreatic cancer cells lacking background BRCA mutations exhibits potential improvement relative to FOLFIRINOX alone, that may be rationalized based on downregulation of key DNA repair pathways. Future studies should explore the possibility of reducing FOLFIRINOX treatment dose, potentially alleviating FOLFIRINOX-related toxicity.