Targeting BCL2 with Venetoclax Enhances the Efficacy of the KRASG12D Inhibitor MRTX1133 in Pancreatic Cancer.

ABSTRACT: MRTX1133 is currently being evaluated in patients with pancreatic ductal adenocarcinoma (PDAC) tumors harboring a KRASG12D mutation. Combination strategies have the potential to enhance the efficacy of MRTX1133 to further promote cell death and tumor regression. In this study, we demonstrated that MRTX1133 increased the levels of the proapoptotic protein BIM in PDAC cells and conferred sensitivity to the FDA-approved BCL2 inhibitor venetoclax. Combined treatment with MRTX1133 and venetoclax resulted in cell death and growth suppression in 3D cultures. BIM was required for apoptosis induced by the combination treatment. Consistently, BIM was induced in tumors treated with MRTX1133, and venetoclax enhanced the efficacy of MRTX1133 in vivo. Venetoclax could also resensitize MRTX1133-resistant

SUBMITTER: Becker JH 

PROVIDER: S-EPMC11532783 | biostudies-literature | 2024 Nov

REPOSITORIES: biostudies-literature