抑制pMAPK14可以克服乙肝病毒对肝癌细胞中索拉非尼的耐药性

StephenW

Transl Oncol. 2018 Mar 7;11(2):511-517. doi: 10.1016/j.tranon.2018.02.015. [Epub ahead of print]
Inhibition of pMAPK14 Overcomes Resistance to Sorafenib in Hepatoma Cells with Hepatitis B Virus.
Witt-Kehati D1, Fridkin A2, Alaluf MB3, Zemel R1, Shlomai A4.
Author information

1
    Felsenstein Medical Research Center and the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
2
    Department of Medicine D, Beilinson hospital Rabin Medical Center, Petah-Tikva, Israel.
3
    Felsenstein Medical Research Center and the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Department of Medicine D, Beilinson hospital Rabin Medical Center, Petah-Tikva, Israel.
4
    Felsenstein Medical Research Center and the Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Department of Medicine D, Beilinson hospital Rabin Medical Center, Petah-Tikva, Israel; The Liver Institute, Beilinson Hospital Rabin Medical Center, Petah-Tikva, Israel. Electronic address: [email protected].

Abstract

Hepatitis B virus (HBV) targets the liver and is a major driver for liver cancer. Clinical data suggest that HBV infection is associated with reduced response to treatment with the multi-kinase inhibitor sorafenib, the first available molecularly targeted anti-hepatocellular carcinoma (HCC) drug. Given that Raf is one of the major targets of sorafenib, we investigated the activation state of the Raf-Mek-Erk pathway in the presence of HBV and in response to sorafenib. Here we show that hepatoma cells with replicating HBV are less susceptible to sorafenib inhibitory effect as compared to cells in which HBV expression is suppressed. However, although HBV replication is associated with increased level of pErk, its blockade only modestly augments sorafenib effect. In contrast, the phosphorylated form of the pro-oncogenic Mitogen-Activated Protein Kinase 14 (pMAPK14), a protein kinase that was recently linked to sorafenib resistance, is induced in sorafenib-treated hepatoma cells in association with HBV X protein expression. Knocking down pMAPK14 results in augmentation of the therapeutic efficacy of sorafenib and largely alleviates resistance to sorafenib in the presence of HBV. Thus, this study suggests that HBV promotes HCC resistance to sorafenib. Combining pMAPK14 inhibitors with sorafenib may be beneficial in patients with HBV-associated HCC.

PMID:
    29524828
DOI:
    10.1016/j.tranon.2018.02.015

StephenW

Transl Oncol。 2018年3月7日; 11（2）：511-517。 doi：10.1016 / j.tranon.2018.02.015。 [电子版提前打印]
抑制pMAPK14可以克服乙肝病毒对肝癌细胞中索拉非尼的耐药性。
Witt-Kehati D1，Fridkin A2，Alaluf MB3，Zemel R1，Shlomai A4。
作者信息

1
    Felsenstein医学研究中心和以色列特拉维夫特拉维夫大学Sackler医学院。
2
    以色列Petah-Tikva的Beilinson医院拉宾医学中心医学系D部。
3
    Felsenstein医学研究中心和以色列特拉维夫特拉维夫大学萨克勒医学院;以色列Petah-Tikva的Beilinson医院拉宾医学中心医学系D部。
4
    Felsenstein医学研究中心和以色列特拉维夫特拉维夫大学萨克勒医学院;以色列Petah-Tikva省Beilinson医院拉宾医学中心医学系D;以色列Petah-Tikva的Beilinson医院Rabin医学中心的肝脏研究所。电子地址：[email protected]。

抽象

乙型肝炎病毒（HBV）靶向肝脏，是肝癌的主要驱动因素。临床数据表明，HBV感染与第一种可用的分子靶向抗肝细胞癌（HCC）药物多激酶抑制剂索拉非尼治疗的反应降低有关。鉴于Raf是索拉非尼的主要靶点之一，我们调查了Raf-Mek-Erk途径在HBV存在和索拉非尼作用下的激活状态。在这里我们显示与HBV表达被抑制的细胞相比，复制HBV的肝细胞瘤细胞对索拉非尼的抑制作用较不敏感。然而，尽管HBV复制与pErk水平增加相关，但其封锁仅适度地增强索拉非尼效应。相比之下，在索拉非尼处理的肝癌细胞中与HBV X蛋白表达相关联，诱导了致癌性丝裂原活化蛋白激酶14（pMAPK14）（一种最近与索拉非尼抗性相关的蛋白激酶）的磷酸化形式。敲低pMAPK14可以增强索拉非尼的治疗效果，并大大减轻HBV存在时对索拉非尼的耐药性。因此，这项研究表明HBV促进HCC对索拉非尼的耐药。联合使用pMAPK14抑制剂和索拉非尼可能对HBV相关HCC患者有益。

结论：
    29524828
DOI：
    10.1016 / j.tranon.2018.02.015