Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Drug Discovery and Design Center, the Center for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
J Clin Invest. 2023 May 1;133(9):e161929. doi: 10.1172/JCI161929.
Aurora A plays a critical role in G2/M transition and mitosis, making it an attractive target for cancer treatment. Aurora A inhibitors showed remarkable antitumor effects in preclinical studies, but unsatisfactory outcomes in clinical trials have greatly limited their development. In this study, the Aurora A inhibitor alisertib upregulated programmed death ligand 1 (PD-L1) expression in a panel of tumor cells both in vitro and in vivo. Upregulation of the checkpoint protein PD-L1 reduced antitumor immunity in immune-competent mice, paradoxically inhibiting the antitumor effects of alisertib. Mechanistically, Aurora A directly bound to and phosphorylated cyclic GMP-AMP synthase (cGAS), suppressing PD-L1 expression in tumor cells. Aurora A inhibition by alisertib activated the cGAS/stimulator of IFN genes (STING)/NF-κB pathway and promoted PD-L1 expression. Combining alisertib with anti-PD-L1 antibody improved antitumor immunity and enhanced the antitumor effects of alisertib in immune-competent mice. Our results, which reveal the immunomodulatory functions of Aurora A inhibitors and provide a plausible explanation for the poor clinical outcomes with their use, offer a potential approach to improve the antitumor efficacy of these inhibitors.
极光激酶 A 在 G2/M 期转换和有丝分裂中起着关键作用，使其成为癌症治疗的一个有吸引力的靶点。在临床前研究中，极光激酶 A 抑制剂显示出显著的抗肿瘤效果，但在临床试验中的不理想结果极大地限制了它们的发展。在这项研究中，极光激酶 A 抑制剂alisertib 在体外和体内的一系列肿瘤细胞中上调程序性死亡配体 1（PD-L1）的表达。检查点蛋白 PD-L1 的上调降低了免疫功能正常的小鼠中的抗肿瘤免疫，反而抑制了 alisertib 的抗肿瘤作用。从机制上讲，极光激酶 A 直接与环鸟苷酸-腺苷酸合酶（cGAS）结合并使其磷酸化，从而抑制肿瘤细胞中 PD-L1 的表达。alisertib 通过抑制极光激酶 A 激活 cGAS/干扰素基因刺激物（STING）/NF-κB 通路，并促进 PD-L1 的表达。alisertib 与抗 PD-L1 抗体联合使用可改善抗肿瘤免疫，并增强免疫功能正常的小鼠中 alisertib 的抗肿瘤作用。我们的研究结果揭示了极光激酶 A 抑制剂的免疫调节功能，并为其临床应用效果不佳提供了合理的解释，为提高这些抑制剂的抗肿瘤疗效提供了一种潜在的方法。
