The clinical therapeutic efficacy toward esophageal squamous cell carcinoma (ESCC) is undesirable, due to the lack of targeted agents. Focal adhesion kinase (FAK), a nonreceptor tyrosine kinase involved in multiple fields of tumorigenesis, recently has been indicated as a promising therapeutic target in ESCC treatment. Here, we revealed that defactinib, a specific FAK inhibitor, effectively suppressed the malignancy of ESCC cells. Mechanistically, defactinib dose and time‐dependently induced the dissociation of phosphoinositide‐3‐kinase (PI3K) from FAK, resultantly led to blockade of protein kinase B (AKT) signaling, and the expression of several oncogenes, such as SOX2, MYC, EGFR, MET, MDM2, or TGFBR2, identified by microarray and real‐time polymerase chain reaction assay. Specifically, this FAK inhibition‐mediated suppression of PI3K/AKT signaling and downstream ESCC specific biomarkers was maintained to 24 h in in vitro experiments to guarantee the treatment durability and efficacy. Importantly, defactinib suppressed tumor growth, metastatic ability, and increased overall survival of xenografted animals without producing significantly systematic toxicity. Our data suggest that FAK inhibition provides an excellent targeted therapy toward ESCC by effectively inhibiting PI3K/AKT pathway and downstream molecular network.

中文翻译：

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黏着斑激酶（FAK）抑制剂-defactinib通过有效阻断PI3K / AKT轴和下游分子网络抑制人食道鳞状细胞癌（ESCC）细胞的恶性进展

由于缺乏靶向药物，对食管鳞状细胞癌（ESCC）的临床治疗效果不理想。粘着斑激酶（FAK）是一种涉及肿瘤发生多个领域的非受体酪氨酸激酶，最近已被证明是ESCC治疗中有希望的治疗靶标。在这里，我们揭示了一种特异的FAK抑制剂defactinib有效抑制了ESCC细胞的恶性肿瘤。从机理上讲，defactinib剂量和时间依赖性地导致磷酸肌醇3激酶（PI3K）从FAK上解离，从而导致蛋白激酶B（AKT）信号传导的阻断，以及几种致癌基因如SOX2，MYC和EGFR的表达，MET，MDM2或TGFBR2，通过微阵列和实时聚合酶链反应测定法鉴定。具体而言，在体外实验中，这种FAK抑制介导的PI3K / AKT信号和下游ESCC特异性生物标志物的抑制作用可维持24小时，以确保治疗的持久性和有效性。重要的是，defactinib可抑制异种移植动物的肿瘤生长，转移能力并提高其总生存率，而不会产生明显的系统毒性。我们的数据表明，FAK抑制可通过有效抑制PI3K / AKT途径和下游分子网络为ESCC提供出色的靶向治疗。