TY  - JOUR
AU  - Zhao, Ben
AU  - Fang, Rui
AU  - Schürmann, Hendrik
AU  - Hemmer, Erik Jan
AU  - Mayer, Gina Lauren
AU  - Trajkovic-Arsic, Marija
AU  - Althoff, Kristina
AU  - Yang, Jiajin
AU  - Godfrey, Laura
AU  - Liffers, Sven T
AU  - Savvatakis, Konstantinos
AU  - Dorsch, Madeleine
AU  - Grüner, Barbara M
AU  - Hahn, Stephan
AU  - Remke, Marc
AU  - Lueong, Smiths S
AU  - Siveke, Jens T
TI  - PLK1 blockade enhances the anti-tumor effect of MAPK inhibition in pancreatic ductal adenocarcinoma.
JO  - Cell reports
VL  - 44
IS  - 4
SN  - 2211-1247
CY  - Maryland Heights, MO
PB  - Cell Press
M1  - DKFZ-2025-00739
SP  - 115541
PY  - 2025
AB  - Despite constitutive Ras/Raf/MAPK pathway activation in most pancreatic ductal adenocarcinomas (PDACs), treatment approaches targeting this pathway have primarily been unsuccessful. We conduct a drug library screen on an MEK inhibitor (MEKi)-resistant PDAC model and perform complementary pathway analysis to identify cellular resistance phenotypes. We use syngeneic models to investigate the molecular determinants of identified drug synergism. Our study reveals an enrichment for the hallmarks of G2/M checkpoints in MEKi-resistant phenotypes from all investigated models. We find overexpression of Polo-like kinase 1 (PLK1) and other G2/M checkpoint-related proteins in MEKi-resistant cells. We identify synergistic activity between MEK and PLK1 inhibition both in vitro and in vivo and mechanistically show that dual inhibition of the PLK1 and MEK pathways activates the JNK/c-JUN pathway. This causes the accumulation of DNA damage, ultimately leading to apoptotic cell death. Dual PLK1/MEK inhibition emerges as a promising targeted approach in PDAC.
KW  - CP: Cancer (Other)
KW  - G1 arrest (Other)
KW  - G2/M checkpoint (Other)
KW  - JNK (Other)
KW  - KRAS (Other)
KW  - MAPK (Other)
KW  - MEK (Other)
KW  - PDAC (Other)
KW  - PDO (Other)
KW  - PLK1 (Other)
KW  - cJUN (Other)
KW  - cell cycle (Other)
KW  - organoids (Other)
KW  - synergism (Other)
KW  - therapy resistance (Other)
KW  - trametinib (Other)
KW  - volasertib (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:40188436
DO  - DOI:10.1016/j.celrep.2025.115541
UR  - https://inrepo02.dkfz.de/record/300286
ER  -