School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan.
Department of Urology, Chung Shan Medical University Hospital, Taichung 40201, Taiwan.
Cells. 2024 Oct 17;13(20):1713. doi: 10.3390/cells13201713.
Renal cell carcinoma (RCC) has diverse pathological subtypes, most of which have a poor prognosis. Patients with advanced RCC require systemic therapies for disease control. Although targeted therapies and immune checkpoint inhibitors have shown therapeutic efficacy, patients eventually succumb to disease progression. Therefore, additional therapies targeting different pathways are needed to provide more therapeutic options for sequential treatment. Our study explored the biological mechanisms and therapeutic outcomes for NPS-1034, a dual MET/AXL inhibitor, in RCC, both in vivo and in vitro. Our results showed that NPS-1034 can significantly inhibit tumor proliferation and induce cancer cell apoptosis. Besides MET and AXL, known targets of NPS-1034, we identified TNFRSF1A as another target gene inhibited by NPS-1034 via antibody arrays. This was further supported by next-generation sequencing, showing that the TNF signaling pathway is one of the most significant NPS-1034-regulated pathways. Furthermore, one of the identified target genes, GADD45A, responsible for NPS-1034 anticancer properties, was significantly associated with patient survival in RCC. GADD45A expression was significantly upregulated via NPS-1034 and downregulated via TNFRSF1A overexpression. Finally, its therapeutic efficacy was demonstrated in vivo, showing that NPS-1034 significantly alleviated the tumor burden and inhibited cell proliferation in a lung metastatic animal model. In conclusion, we explored the therapeutic mechanism of NPS-1034 and found that it targets not only MET and AXL but also TNFRSF1A. In a lung metastatic animal model, we confirmed that NPS-1034 is a potential candidate for systemic therapy in RCC.
肾细胞癌（RCC）具有多种病理亚型，大多数预后不良。晚期 RCC 患者需要进行系统治疗以控制疾病。尽管靶向治疗和免疫检查点抑制剂已显示出治疗效果，但患者最终仍会因疾病进展而死亡。因此，需要针对不同途径的其他治疗方法为序贯治疗提供更多的治疗选择。我们的研究探讨了 NPS-1034（一种双重 MET/AXL 抑制剂）在体内和体外对 RCC 的生物学机制和治疗效果。我们的结果表明，NPS-1034 可显著抑制肿瘤增殖并诱导癌细胞凋亡。除了 NPS-1034 的已知靶点 MET 和 AXL 外，我们还通过抗体阵列鉴定出 TNFRSF1A 是另一个受 NPS-1034 抑制的靶基因。下一代测序进一步支持了这一发现，表明 TNF 信号通路是 NPS-1034 调节的最重要通路之一。此外，鉴定出的靶基因之一 GADD45A 负责 NPS-1034 的抗癌特性，与 RCC 患者的生存显著相关。NPS-1034 可显著上调 GADD45A 的表达，而 TNFRSF1A 的过表达则可下调其表达。最后，在体内证明了其治疗效果，表明 NPS-1034 可显著减轻肿瘤负担并抑制肺转移动物模型中的细胞增殖。总之，我们探讨了 NPS-1034 的治疗机制，发现它不仅靶向 MET 和 AXL，还靶向 TNFRSF1A。在肺转移动物模型中，我们证实 NPS-1034 是 RCC 系统治疗的潜在候选药物。
