A multi-kinase inhibitor APG-2449 enhances the antitumor effect of ibrutinib in esophageal squamous cell carcinoma via EGFR/FAK pathway inhibition
A multi-kinase inhibitor APG-2449 enhances the antitumor effect of ibrutinib in esophageal squamous cell carcinoma via EGFR/FAK pathway inhibition
复制标题
多激酶抑制剂APG-2449通过抑制EGFR/FAK通路增强依鲁替尼对食管鳞癌的抗肿瘤作用
DOI：
10.1016/j.bcp.2020.114318
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发表时间：
2021-01-01
影响因子：
5.8
通讯作者：
Yang, Da-Jun
中科院分区：
文献类型：
--
作者：
Luo, Qiu-Yun;Zhou, Su-Na;Yang, Da-Jun
食管鳞状细胞癌是我国最常见的恶性肿瘤之一，预后差，缺乏有效的靶向治疗。据报道，伊曲替尼在伴有MYC和/或ERBB 2扩增的ESCC中具有抗癌活性。本研究通过体内外实验，探讨新型多激酶抑制剂APG-2449与伊曲替尼对食管鳞癌的协同抗肿瘤作用，并阐明其作用机制。我们发现APG-2449对ESCC有抗肿瘤作用。APG-2449与伊曲替尼联合应用对食管鳞癌细胞株的细胞活力具有协同抑制作用。APG-2449联合伊曲替尼显著抑制ESCC细胞增殖和迁移。此外，我们观察到伊曲替尼与APG-2449联合使用可诱导更多的癌细胞阻滞于G1/S期和凋亡。在机制上，单独使用伊曲替尼可降低EGFR及其下游途径MEK/ERK的磷酸化水平。APG-2449与伊曲替尼联合治疗可显著下调MEK/ERK和AKT的磷酸化水平。在ESCC异种移植模型中，伊布替尼或APG-2449单药治疗在延缓肿瘤生长方面相当，而联合治疗对肿瘤生长的抑制作用更显着。我们的数据有力地表明，APG-2449与伊曲替尼联合治疗可为ESCC患者提供一种有效的治疗策略，值得进一步临床研究。
Esophageal squamous cell carcinoma (ESCC) is one of the most common types of cancer in China, with poor prognosis and lack of effective targeted therapy. It has been reported that ibrutinib possesses anticancer activity in ESCC with MYC and/or ERBB2 amplification. Here we explored the synergistic antitumor effect of a novel multi-kinase inhibitor APG-2449 with ibrutinib in ESCC and clarified the mechanism of the combination effect through in vitro and in vivo experiment. We found that APG-2449 exerted antitumor effect in ESCC. APG-2449 combined with ibrutinib showed synergistic inhibition of cell viability in ESCC cell lines. APG-2449 combined with ibrutinib dramatically inhibited the proliferation and migration of ESCC cells. Furthermore, we observed that ibrutinib combined with APG-2449 could induce more cancer cells arrested in the G1/S phase and apoptosis. In terms of mechanism, ibrutinib alone could decrease the phosphorylation level of EGFR and its downstream pathway of MEK/ERK. The combination therapy of APG-2449 and ibrutinib could significantly down-regulate the phosphorylation level of MEK/ERK and AKT. In ESCC xenotransplantation models, single therapy with either ibrutinib or APG-2449 was equivalent in delaying tumor growth, while the combination therapy suppressed tumor growth more significantly. Our data strongly suggest that the combination therapy of APG-2449 and ibrutinib can provide an effective therapeutic strategy for ESCC patients, which deserved further clinical investigation.