The MEK1/2 Inhibitor Pimasertib Enhances Gemcitabine Efficacy in Pancreatic Cancer Models by Altering Ribonucleotide Reductase Subunit-1 (RRM1)

摘要: Purpose:Gemcitabine, a nucleoside analogue, is an important treatment for locally advanced and metastatic pancreatic ductal adenocarcinoma (PDAC), but provides only modest survival benefit. Targeting downstream effectors of the RAS/ERK signalling pathway by direct inhibition MEK1/2 proteins promising therapeutic strategy, since aberrant activation this occurs frequently in PDAC. In study, ability pimasertib, selective allosteric inhibitor, to enhance gemcitabine efficacy was tested molecular mechanism their interaction investigated. Experimental Design: Cell apoptosis were assessed MTT Caspase 3/7 Glo assays human cancer cell lines. Protein expression detected immunoblotting. The vivo sensitivity with pimasertib evaluated orthotopic model tumor. Results:Synergistic activity observed when combined sequentially cells. particular, reduced ribonucleotide reductase subunit 1 (RRM1) protein associated gemcitabine. Pre-treatment MG132 impaired reduction RRM1 induced suggesting degraded post-translationally. Immunoprecipitation indicated enhanced MDM2-mediated polyubiquitination through lys48-mediated linkage following treatment, effect part mediated AKT. Finally, combination caused significant tumor growth delays model, down-regulation pimasertib-treated mice. Conclusions:These results confirm role response indicate MEK as potential target sensitize therapy