NPS-1034 Exerts Therapeutic Efficacy in Renal Cell Carcinoma Through Multiple Targets of MET, AXL, and TNFRSF1A Signaling in a Metastatic Model.

IF 5.1 2区 生物学 Q2 CELL BIOLOGY
Cells Pub Date : 2024-10-17 DOI:10.3390/cells13201713
Ya-Chuan Chang, Chien-Te Liu, Chia-Ying Yu, Wen-Wei Sung
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Abstract

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.

NPS-1034在转移模型中通过MET、AXL和TNFRSF1A信号的多个靶点对肾细胞癌发挥疗效
肾细胞癌(RCC)有多种病理亚型,其中大多数预后不良。晚期 RCC 患者需要接受全身治疗以控制病情。尽管靶向疗法和免疫检查点抑制剂已显示出疗效,但患者最终还是会因疾病进展而死亡。因此,需要更多针对不同通路的疗法,为序贯治疗提供更多治疗选择。我们的研究探讨了MET/AXL双重抑制剂NPS-1034在RCC体内和体外的生物学机制和治疗效果。结果表明,NPS-1034 能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,我们还通过抗体阵列发现 TNFRSF1A 是 NPS-1034 抑制的另一个靶基因。下一代测序进一步证实了这一点,表明 TNF 信号通路是 NPS-1034 最重要的调控通路之一。此外,NPS-1034抗癌特性的靶基因之一GADD45A与RCC患者的存活率显著相关。GADD45A的表达在NPS-1034的作用下明显上调,而在TNFRSF1A过表达的作用下则明显下调。最后,NPS-1034的疗效在体内得到了证实,在肺转移动物模型中,NPS-1034能明显减轻肿瘤负担并抑制细胞增殖。总之,我们探索了 NPS-1034 的治疗机制,发现它不仅能靶向 MET 和 AXL,还能靶向 TNFRSF1A。在肺转移动物模型中,我们证实了 NPS-1034 是 RCC 全身治疗的潜在候选药物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cells
Cells Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)
CiteScore
9.90
自引率
5.00%
发文量
3472
审稿时长
16 days
期刊介绍: Cells (ISSN 2073-4409) is an international, peer-reviewed open access journal which provides an advanced forum for studies related to cell biology, molecular biology and biophysics. It publishes reviews, research articles, communications and technical notes. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. Full experimental and/or methodical details must be provided.
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