VMP1 in Pancreatic Cancer: A Rationale for Targeted Protein Degradation

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with a five-year survival rate below 12%. The intrinsic chemoresistance of PDAC underscores the urgent need for novel therapeutic targets. Vacuole Membrane Protein 1 (VMP1) is a transmembrane protein that functions as a master regulator of autophagy, phospholipid scrambling, and membrane contact site dynamics. VMP1 is markedly overexpressed in PDAC downstream of oncogenic KRAS. Recent work from our group demonstrated that VMP1 is regulated by non-degradative polyubiquitination. Here, we review VMP1 biology and its regulation by the ubiquitin system, proposing it as an attractive candidate for Targeted Protein Degradation (TPD). We discuss how emerging TPD platforms could be leveraged to selectively eliminate VMP1, thereby establishing a conceptual framework for next-generation therapeutic approaches in pancreatic cancer.