Luo Min, Xia Yuhui, Wang Fang, Zhang Hong, Su Danting, Su Chaoyue, Yang Chuan, Wu Shaocong, An Sainan, Lin Suxia, Fu Liwu
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
Pharmacy College, Guangzhou Medical University, Guangzhou 510182, China.
Acta Pharm Sin B. 2021 Oct;11(10):3120-3133. doi: 10.1016/j.apsb.2021.03.010. Epub 2021 Mar 9.
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 and models in non-small cell lung carcinoma (NSCLC) cells. Mechanistically, PD0325901 or shRNA- 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 and 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.
ERK通路调节程序性死亡配体-1（PD-L1）的表达，而这与程序性死亡-1（PD-1）/PD-L1阻断疗法的反应相关。因此可以推断，ERK抑制剂能够增强PD-1抑制剂在癌症免疫治疗中的疗效。在本研究中，口服强效ERK抑制剂PD0325901显著增强了PD-1抗体在非小细胞肺癌（NSCLC）细胞及模型中的疗效。机制上，PD0325901或shRNA显著下调了NSCLC细胞中PD-L1的表达，并增加了肿瘤组织中CD3+T细胞的浸润及功能。NSCLC患者中p-ERK1/2表达与PD-L1表达呈正相关。并且观察到p-ERK1/2表达低的患者对PD-1/PD-L1阻断疗法有较高的反应率。我们的结果表明，ERK抑制剂PD0325901能够增强PD-1阻断对NSCLC细胞及模型的疗效。并且ERK抑制剂如PD0325901与PD-1/PD-L1阻断的联合是一种有前景的治疗方案，鼓励在NSCLC患者治疗中进一步证实。
