ERK pathway regulated the programmed death ligand-1(PD-L1)expression which was linked to the response of programmed death-1(PD-1)/PD-L1 blockade therapy.So it is deducible that ERK inhibitor could enhance the efficacy...ERK pathway regulated the programmed death ligand-1(PD-L1)expression which was linked to the response of programmed death-1(PD-1)/PD-L1 blockade therapy.So it is deducible that ERK inhibitor could enhance the efficacy of PD-1 inhibitor in cancer immunotherapy.In this study,PD0325901,an oral potent ERK inhibitor,strongly enhanced the efficacy of PD-1 antibody in vitro and in vivo models in non-small cell lung carcinoma(NSCLC)cells.Mechanistically,PD0325901 or shRNA-ERK1/2 significantly downregulated the PD-L1 expression in NSCLC cells and increased the CD3+T cells infiltration and functions in tumor tissue.There was a positive correlation between the p-ERK1/2 expression and PD-L1 expression in patients with NSCLC.And the patients with low p-ERK1/2 expression were observed a high response rate of PD-1/PD-L1 blockage therapy.Our results demonstrate that PD0325901,an ERK inhibitor,can enhance the efficacy of PD-1 blockage against NSCLC in vitro and in vivo models.And the combination of ERK inhibitor such as PD0325901 and PD-1/PD-L1 blockage is a promising regimen and encouraged to be further confirmed in the treatment of patients with NSCLC.展开更多
基金the grants from the National Science&Technology Major Project“Key New Drug Creation and Manufacturing Program”,China(No:2018ZX09711002)the National Natural Science Foundation of China(No:81673463)。
文摘ERK pathway regulated the programmed death ligand-1(PD-L1)expression which was linked to the response of programmed death-1(PD-1)/PD-L1 blockade therapy.So it is deducible that ERK inhibitor could enhance the efficacy of PD-1 inhibitor in cancer immunotherapy.In this study,PD0325901,an oral potent ERK inhibitor,strongly enhanced the efficacy of PD-1 antibody in vitro and in vivo models in non-small cell lung carcinoma(NSCLC)cells.Mechanistically,PD0325901 or shRNA-ERK1/2 significantly downregulated the PD-L1 expression in NSCLC cells and increased the CD3+T cells infiltration and functions in tumor tissue.There was a positive correlation between the p-ERK1/2 expression and PD-L1 expression in patients with NSCLC.And the patients with low p-ERK1/2 expression were observed a high response rate of PD-1/PD-L1 blockage therapy.Our results demonstrate that PD0325901,an ERK inhibitor,can enhance the efficacy of PD-1 blockage against NSCLC in vitro and in vivo models.And the combination of ERK inhibitor such as PD0325901 and PD-1/PD-L1 blockage is a promising regimen and encouraged to be further confirmed in the treatment of patients with NSCLC.
