Despite major advances in non-small-cell lung cancer (NSCLC) treatment, the five-year survival rates for patients with non-oncogene-driven tumors remain low, necessitating combinatory approaches to improve outcomes. Our prior high-throughput RNAi screening identified Aurora kinase A (AURKA) as a potential key player in cisplatin resistance. In this study, we investigated AURKA’s role in platinum and radiation sensitivity in multiple NSCLC cell lines and xenograft mouse models, as well as its effect on immune checkpoints, including PD-L1, B7x, B7-H3, and HHLA2. Of 94 NSCLC patient tumor specimens, 91.5% tested positive for AURKA expression, with 34% showing moderate-to-high levels. AURKA expression was upregulated following cisplatin treatment in NSCLC cell lines PC9 and A549. Both AURKA inhibition by alisertib and inducible AURKA knockdown potentiated the cytotoxic effects of cisplatin and radiation, leading to tumor regression in doxycycline-inducible xenograft mice. Co-treated cells exhibited increased DNA double-strand breaks, apoptosis, and senescence. Additionally, AURKA inhibition alone by alisertib increased PD-L1 and B7-H3 expression. In conclusion, our study demonstrates that AURKA inhibition enhances the efficacy of platinum-based chemotherapy in NSCLC cells and modulates the expression of multiple immune checkpoints. Therefore, combinatory regimens with AURKA inhibitors should be strategically designed and further studied within the evolving landscape of chemo-immunotherapy.
尽管非小细胞肺癌（NSCLC）治疗已取得重大进展，但非致癌基因驱动型肿瘤患者的五年生存率仍然较低，这需要通过联合治疗策略来改善预后。我们先前的高通量RNA干扰筛选发现极光激酶A（AURKA）可能是顺铂耐药的关键因子。本研究通过多种NSCLC细胞系和异种移植小鼠模型，探讨了AURKA在铂类药物及放射敏感性中的作用，并分析其对PD-L1、B7x、B7-H3和HHLA2等免疫检查点的影响。在94例NSCLC患者肿瘤样本中，91.5%呈AURKA阳性表达，其中34%呈中高水平表达。在PC9和A549细胞系中，顺铂处理后AURKA表达显著上调。使用阿利塞替抑制AURKA或诱导性敲低AURKA表达，均能增强顺铂与放射治疗的细胞毒性效应，并在多西环素诱导的异种移植小鼠模型中实现肿瘤消退。联合治疗组细胞表现出DNA双链断裂增加、细胞凋亡和衰老加剧。此外，单用阿利塞替抑制AURKA即可上调PD-L1和B7-H3表达。综上，本研究表明抑制AURKA能增强铂类化疗在NSCLC细胞中的疗效，并调控多种免疫检查点表达。因此，在化疗-免疫治疗协同发展的背景下，应战略性设计AURKA抑制剂的联合治疗方案并开展深入研究。
肿瘤(癌症)患者之家