Concurrent inhibition of pBADS99 synergistically improves MEK inhibitor efficacy in KRAS^G12D-mutant pancreatic ductal adenocarcinoma.

ABSTRACT: Therapeutic targeting of KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) has remained a significant challenge in clinical oncology. Direct targeting of KRAS has proven difficult, and inhibition of the KRAS effectors have shown limited success due to compensatory activation of survival pathways. Being a core downstream effector of the KRAS-driven p44/42 MAPK and PI3K/AKT pathways governing intrinsic apoptosis, BAD phosphorylation emerges as a promising therapeutic target. Herein, a positive association of the pBADS99/BAD ratio with higher disease stage and worse overall survival of PDAC was observed. Homology-directed repair of BAD to BADS99A or small molecule inhibition of BADS99 phosphorylation by NCK significantly reduced PDAC cell viability by promoting cell cycle arrest and apoptos

SUBMITTER: Tan YQ 

PROVIDER: S-EPMC10897366 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature