Modulation of radiosensitivity by myoferlin pharmacological targeting in human pancreatic cancer cell lines.

Pancreatic ductal adenocarcinoma (PDAC) will become the second leading cause of cancer-related deaths by 2030. Myoferlin is a protein involved in membrane fusion and in membrane receptors recycling and is overexpressed in PDAC where it was reported to be required for an optimal cell growth. We used an innovative small compound (WJ460) to target myoferlin in PDAC cell lines and reported the triggering of ferroptosis, involving mitochondrial iron pool. Based on those results, we believe we revealed a pancreatic cell vulnerability that can be exploited in the treatment of patients with PDAC. Indeed, the alteration of the mitochondrial redox balance is a pathway followed to sensitize cancer cells to radiotherapy. Radiotherapy alone or combined with chemotherapy is a therapeutic modality of the PDAC. Our working hypothesis is that inhibition of myoferlin function sensitizes PDAC cancer cells to radiotherapy. A preliminary analysis carried out using the MiaPaCa-2 cell line demonstrated a significative synergy between WJ460 and irradiation for different combinations. With the aim if increasing the clinical relevance of the project, the various selected combinations of WJ460 and irradiation will be applied first to heterotopic spheroids and then PDAC organoids. Besides, to understand the mechanism behind the radiosensitization observed during treatment with WJ460, we analyzed in silico TCGA data obtained from PDAC patients that indicated a frequent and significative co-occurrence of myoferlin gene alteration with the alteration of genes implicated in DNA repair. In addition, RNA sequencing was performed. The bioinformatic analysis of the results revealed the alteration of gene sets linked to the G2/M phase arrest, considered as increasing radiosensitization. Pharmacological manipulation of myoferlin improves radiosensitivity in vitro. Further work is required to fully understand this discovery and translate these findings into clinical practice.