BACKGROUND Chemo-resistance in hepatocellular carcinoma (HCC) is a major problem, and acquired drug resistance prevents cancer therapies from achieving complete responses. Molecular targeting therapy presents an opportunity to impede tumor through combination or sequential therapy, while the accurate effect is vague. METHODS The efficacy of combinations between oxaliplatin and anti-cancer molecular targeting drugs was screened. Strangely, the combined chemotherapy with oxaliplatin and saracatinib induced significantly antagonistic effects. Then the antitumor effects of combined treatment with saracatinib and oxaliplatin were confirmed in wide type HCC as well as in saracatinib- and oxaliplatin-resistant HCC. RNA sequencing was used to explore the resistance mechanism, and the roles of ATP-binding cassette transporter G1 (ABCG1) and Wnt signaling in oxaliplatin resistance were confirmed. RESULTS Chemotherapy with oxaliplatin and saracatinib individually induced strong anti-HCC effects, while combined or sequential treatment of HCC cells with these two drugs exhibited reduced efficacy compared to treatment with the single drugs. And it was saracatinib treatment caused oxaliplatin resistance. RNA sequencing revealed 458 genes that were altered by treatment with saracatinib and oxaliplatin. Of these, the gene encoding ABCG1 and Wnt-associated genes were significantly upregulated. Upregulation of ABCG1 and oxaliplatin resistance were associated with activation of Wnt signaling. Interference with ABCG1 expression or inhibition of Wnt signaling resulted in reversal of the saracatinib-induced oxaliplatin resistance in HCC. CONCLUSIONS These studies demonstrated that combined or sequential chemotherapy with oxaliplatin and saracatinib reduced antitumor efficacy, and this antagonism was attributed to the activation of Wnt signaling and upregulation of ABCG1 by saracatinib.

中文翻译：

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沙拉替尼通过上调Wnt-ABCG1信号传导在肝细胞癌中增强了奥沙利铂耐药性。

背景技术肝细胞癌（HCC）中的化学抗性是一个主要问题，并且获得性抗药性阻止了癌症疗法获得完全的应答。分子靶向疗法提供了通过联合或序贯疗法阻止肿瘤的机会，而准确的效果却模糊不清。方法筛选奥沙利铂与抗癌分子靶向药物联用的疗效。奇怪的是，将奥沙利铂和萨拉卡替尼联合化疗可产生明显的拮抗作用。然后在宽型HCC以及耐抗沙拉替尼和奥沙利铂的HCC中证实了与saracatatinib和奥沙利铂联合治疗的抗肿瘤作用。RNA测序用于探索耐药机制，并确认了ATP结合盒转运蛋白G1（ABCG1）和Wnt信号在奥沙利铂耐药中的作用。结果奥沙利铂和萨拉卡替尼的化学疗法分别诱导了强大的抗HCC作用，而与这两种药物相比，联合或顺序治疗这两种药物对HCC细胞的疗效降低。而且它是萨拉卡替尼治疗引起的奥沙利铂耐药性。RNA测序揭示了458个基因，这些基因通过使用saracatinib和奥沙利铂治疗而改变。其中，编码ABCG1和Wnt相关基因的基因显着上调。ABCG1和奥沙利铂耐药性的上调与Wnt信号的激活有关。干扰ABCG1的表达或抑制Wnt信号导致了肝癌中saracatinib诱导的奥沙利铂耐药性的逆转。结论这些研究表明，与奥沙利铂和萨拉卡替尼联合或顺序化疗可降低抗肿瘤功效，这种拮抗作用归因于萨拉克替尼激活Wnt信号和上调ABCG1。