核受体共激活因子5的抑制克服了由蛋白激酶b驱动的获得性lenvatinib耐药,雷帕霉素信号在肝细胞癌中的哺乳动物靶点。

IF 2.2 4区 医学 Q3 ONCOLOGY
Hongyuan Zhou, Qin Zhang, Lu Yang, Zhaolong Pan, Haijing Zheng, Zewu Zhang, Dongyang Li, Guangtao Li, Xiaomeng Liu, Xu Bao, Chen Liu, Wei Zhang
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引用次数: 0

摘要

Lenvatinib是一种多受体酪氨酸激酶抑制剂,最近被批准用于肝细胞癌(HCC)的一线治疗。虽然lenvatinib显示出显著的治疗效果,但耐药性破坏了其持续的肿瘤控制潜力。lenvatinib有限的临床应用强调了阐明耐药机制的迫切必要性。我们建立了lenvatinib耐药细胞系,并研究了其生物学特性的变化。下一代测序鉴定lenvatinib耐药相关基因。Western blots证实了这些基因的参与。利用慢病毒技术,我们构建了具有低核受体共激活因子5 (NCOA5)的细胞系,这是一个关键的耐药相关基因,以探索潜在的耐药机制。此外,我们建立了一个皮下肝癌异种移植肿瘤模型来探索逆转耐药性的策略。我们的研究表明,HCC细胞通过激活NCOA5获得对lenvatinib的抗性,从而刺激NCOA5蛋白激酶b -哺乳动物雷帕霉素靶点(AKT-mTOR)轴。此外,HCC标本的临床评估建立了NCOA5通路的激活与lenvatinib治疗反应之间的相关性。mTOR抑制剂依维莫司与lenvatinib和依维莫司联合在体内和体外对HCC具有显著的协同作用。HCC细胞通过激活NCOA5-AKT-mTOR途径对lenvatinib产生耐药性。lenvatinib与依维莫司联合治疗是克服获得性耐药的一种有希望的策略,从而提高lenvatinib的临床疗效。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Inhibition of nuclear receptor coactivator 5 overcomes acquired lenvatinib resistance driven by protein kinase B-mammalian target of rapamycin signaling in hepatocellular carcinoma.

Lenvatinib, a multiple-receptor tyrosine kinase inhibitor, has gained recent approval for its use as a first-line treatment of hepatocellular carcinoma (HCC). While lenvatinib demonstrates notable therapeutic efficacy, the drug resistance undermines its sustained tumor control potential. The restricted clinical utility of lenvatinib underscores the imperative necessity to elucidate the mechanisms underpinning drug resistance. We established lenvatinib-resistant cell lines and investigated the changes in their biological characteristics. Next-generation sequencing was performed to identify genes associated with lenvatinib resistance. Western blots were utilized to confirm the involvement of these genes. Using lentiviral technology, we generated cell lines with lowered nuclear receptor coactivator 5 (NCOA5), a pivotal drug resistance-related gene, to explore the underlying resistance mechanism. Moreover, we developed a subcutaneous HCC xenograft tumor model to explore strategies for reversing drug resistance. Our study showed that HCC cells acquire resistance to lenvatinib through the activation of NCOA5, thereby stimulating the NCOA5-Protein Kinase B-mammalian target of rapamycin (AKT-mTOR) axis. Furthermore, the clinical evaluation of HCC specimens established a correlation between the activation of the NCOA5 pathway and the response to lenvatinib treatment. Everolimus, an mTOR inhibitor, in combination with lenvatinib and everolimus, exerted significant synergistic effects against HCC in vivo and in vitro. HCC cells develop resistance to lenvatinib by activating the NCOA5-AKT-mTOR pathway. The combination therapy of lenvatinib with everolimus is a promising strategy to overcome acquired resistance, thereby enhancing the clinical efficacy of lenvatinib.

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来源期刊
Anti-Cancer Drugs
Anti-Cancer Drugs 医学-药学
CiteScore
3.80
自引率
0.00%
发文量
244
审稿时长
3 months
期刊介绍: Anti-Cancer Drugs reports both clinical and experimental results related to anti-cancer drugs, and welcomes contributions on anti-cancer drug design, drug delivery, pharmacology, hormonal and biological modalities and chemotherapy evaluation. An internationally refereed journal devoted to the fast publication of innovative investigations on therapeutic agents against cancer, Anti-Cancer Drugs aims to stimulate and report research on both toxic and non-toxic anti-cancer agents. Consequently, the scope on the journal will cover both conventional cytotoxic chemotherapy and hormonal or biological response modalities such as interleukins and immunotherapy. Submitted articles undergo a preliminary review by the editor. Some articles may be returned to authors without further consideration. Those being considered for publication will undergo further assessment and peer-review by the editors and those invited to do so from a reviewer pool.
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