Center for Applied Biomedical Research (CRBA), S.Orsola-Malpighi University Hospital, Bologna, Italy.
Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
Br J Cancer. 2019 Mar;120(6):601-611. doi: 10.1038/s41416-018-0375-4. Epub 2019 Feb 15.
Sorafenib is the first targeted agent proven to improve survival of patients with advanced hepatocellular carcinoma (HCC) and it has been used in first line treatments with heterogeneous response across patients. Most of the promising agents evaluated in first-line or second-line phase III trials for HCC failed to improve patient survival. The absence of molecular characterisation, including the identification of pathways driving resistance might be responsible for these disappointing results.
2D DIGE and MS analyses were used to reveal proteomic signatures resulting from Notch3 inhibition in HepG2 cells, combined with brivanib treatment. The therapeutic potential of Notch3 inhibition combined with brivanib treatment was also demonstrated in a rat model of HCC and in cell lines derived from different human cancers.
Using a proteomic approach, we have shown that Notch3 is strongly involved in brivanib resistance through a p53-dependent regulation of enzymes of the tricarboxylic acid (TCA), both in vitro and in vivo.
We have demonstrated that regulation of the TCA cycle is a common mechanism in different human cancers, suggesting that Notch3 inhibitors combined with brivanib treatment may represent a strong formulation for the treatment of HCC as well as Notch3-driven cancers.
索拉非尼是首个被证实能提高晚期肝细胞癌（HCC）患者生存的靶向药物，已被用于一线治疗，但患者的反应存在异质性。大多数在 HCC 一线或二线 III 期试验中评估的有前途的药物未能改善患者的生存。缺乏分子特征，包括确定导致耐药性的途径，可能是这些令人失望的结果的原因。
使用 2D DIGE 和 MS 分析来揭示 Notch3 抑制在 HepG2 细胞中与 brivanib 联合治疗的蛋白质组学特征。Notch3 抑制联合 brivanib 治疗在 HCC 大鼠模型和源自不同人类癌症的细胞系中也显示出了治疗潜力。
我们使用蛋白质组学方法表明，Notch3 通过 p53 依赖性调节三羧酸（TCA）中的酶强烈参与 brivanib 耐药，无论是在体外还是体内。
我们已经证明，三羧酸循环的调节是不同人类癌症中的一种常见机制，这表明 Notch3 抑制剂联合 brivanib 治疗可能是治疗 HCC 以及 Notch3 驱动的癌症的一种强有力的方案。
