The combination of BCL-xL PROTAC and mTOR inhibitor sensitizes pancreatic ductal adenocarcinoma to KRAS^G12D inhibitor treatment by enhancing apoptosis induction.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a five-year survival rate of approximately 13%, partly because of limited treatment options and resistance to therapies. Although the recently discovered KRAS G12D inhibitor MRTX1133 has shown promise for PDAC treatment in preclinical studies, its clinical efficacy as a single agent is expected to be limited, as is the case with KRAS G12C inhibitors. Therefore, in this study, we evaluated potential combination strategies to enhance the therapeutic effect of MRTX1133. We rationally combined MRTX1133 with the BCL-xL proteolysis-targeting chimera (PROTAC) DT2216 and the mTOR inhibitor everolimus, which significantly potentiated the anti-tumor activity of MRTX1133 in multiple G12D-mutated PDAC cells in vitro by enhancin

SUBMITTER: Miyan J 

PROVIDER: S-EPMC12803287 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature