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首页> 外文期刊>Biochemical Pharmacology >A multi-kinase inhibitor APG-2449 enhances the antitumor effect of ibrutinib in esophageal squamous cell carcinoma via EGFR/FAK pathway inhibition
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A multi-kinase inhibitor APG-2449 enhances the antitumor effect of ibrutinib in esophageal squamous cell carcinoma via EGFR/FAK pathway inhibition

机译：多激酶抑制剂APG-2449通过EGFR / FAK途径抑制增强了Ibrutinib在食管鳞状细胞癌中的抗肿瘤效应

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摘要

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.
机译：食管鳞状细胞癌（ESCC）是中国最常见的癌症类型之一，预后差和缺乏有效的目标治疗。据报道，Ibrutinib在ESCC中具有MYC和/或ERBB2扩增具有抗癌活动。在这里，我们探讨了一种新型多激酶抑制剂APG-2449与Ibrutinib在Ebrutinib中的协同抗肿瘤效果，并通过体外和体内实验阐明了组合效应的机制。我们发现APG-2449在ESCC中施加抗肿瘤效果。 APG-2449结合Ibrutinib在ESCC细胞系中表现出对细胞活力的协同抑制。 APG-2449与Ibrutinib相结合显着抑制了ESCC细胞的增殖和迁移。此外，我们观察到Ibrutinib结合APG-2449可以诱导更多在G1 / S期和凋亡中被捕的癌细胞。就机制而言，单独的伊布洛尼可降低EGFR的磷酸化水平及其MEK / ERK的下游途径。 APG-2449和Ibrutinib的组合治疗可以显着降低MEK / ERK和AKT的磷酸化水平。在ESCC异种传​​导模型中，具有易替尼或APG-2449的单一治疗相当于延迟肿瘤生长，而组合治疗抑制肿瘤生长更显着。我们的数据强烈表明，APG-2449和Ibrutinib的组合治疗可以为ESCC患者提供有效的治疗策略，其应得到进一步的临床调查。

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  • 来源
    《Biochemical Pharmacology》 |2021年第1期|共12页
  • 作者

    Luo Qiu-Yun; Zhou Su-Na; Pan Wen-Tao; Sun Jian; Yang Li-Qiong; Zhang Lin; Qiu Miao-Zhen; Yang Da-Jun;

  • 作者单位

    Sun Yat Sen Univ Dept Expt Res Collaborat Innovat Ctr Canc Med State Key Lab Oncol South China;

    Sun Yat Sen Univ Dept Expt Res Collaborat Innovat Ctr Canc Med State Key Lab Oncol South China;

    Sun Yat Sen Univ Dept Expt Res Collaborat Innovat Ctr Canc Med State Key Lab Oncol South China;

    Sun Yat Sen Univ Dept Clin Res Collaborat Innovat Ctr Canc Med State Key Lab Oncol South China;

    Sun Yat Sen Univ Dept Expt Res Collaborat Innovat Ctr Canc Med State Key Lab Oncol South China;

    Sun Yat Sen Univ Dept Clin Lab Collaborat Innovat Ctr Canc Med State Key Lab Oncol South China;

    Sun Yat Sen Univ Dept Med Oncol Collaborat Innovat Ctr Canc Med State Key Lab Oncol South China;

    Sun Yat Sen Univ Dept Expt Res Collaborat Innovat Ctr Canc Med State Key Lab Oncol South China;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药理学;
  • 关键词

    FAK; Ibrutinib; EGFR; ESCC; Combination therapy;

    机译：Fak;Ibrutinib;EGFR;ESCC;联合治疗;

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