The application of tyrosine kinase inhibitors (TKIs) to the epidermal growth factor receptor (EGFR) has been proven to be highly effective for non‐small‐cell lung cancer (NSCLC). However, patients often evolve into acquired resistance. The secondary mutations in EGFR account for nearly half of the acquired resistance. While the remaining 50% of patients exhibit tolerance to EGFR‐TKIs with unclear mechanism(s). Cylindromatosis (CYLD), a deubiquitinase, functions as a tumor suppressor to regulate cell apoptosis, proliferation, and immune response, and so on. The role of CYLD in NSCLC EGFR‐TKI resistance remains elusive. Here, we found CYLD was upregulated in PC‐9 cells, whereas downregulated in PC‐9 acquired gefitinib‐resistant (PC‐9/GR) cells in response to the treatment of gefitinib, which is consistent with the results in the Gene Expression Omnibus database. Overexpression of CYLD promoted a more apoptotic death ratio in PC‐9/GR cells than that in PC‐9 cells. In addition, silencing the expression of CYLD resulted in an increase of the expression level of interleukin‐6, transforming growth factor‐β and tumor necrosis factor‐α, which may contribute to acquired resistance of PC‐9 cells to gefitinib. Taken together, our data in vitro demonstrate that PC‐9/GR cells downregulated CYLD expression, enhanced subsequent CYLD‐dependent antiapoptotic capacity and inflammatory response, which may provide a possible target for acquired gefitinib‐resistant treatment in NSCLC.

中文翻译：

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在吉非替尼治疗的NSCLC PC-9细胞中，CYLD的表达降低会促进细胞存活和炎症：靶向CYLD可能对吉非替尼治疗的获得性耐药性有益。

酪氨酸激酶抑制剂（TKIs）应用于表皮生长因子受体（EGFR）已被证明对非小细胞肺癌（NSCLC）非常有效。但是，患者常常演变为获得性抵抗力。EGFR的继发突变占获得性耐药的近一半。其余50％的患者表现出对EGFR-TKI的耐受性，但机制尚不清楚。圆柱化病（CYLD）是一种去泛素酶，可作为肿瘤抑制因子来调节细胞凋亡，增殖和免疫反应等。CYLD在NSCLC EGFR-TKI耐药中的作用仍然难以捉摸。在这里，我们发现CYLD在PC-9细胞中上调，而在PC-9获得性吉非替尼耐药（PC-9 / GR）细胞中由于对吉非替尼的治疗而下调，与Gene Expression Omnibus数据库中的结果一致。CYLD的过度表达促进PC-9 / GR细胞的凋亡死亡率高于PC-9细胞。另外，沉默CYLD的表达导致白介素6，转化生长因子β和肿瘤坏死因子α的表达水平增加，这可能有助于PC-9细胞获得对吉非替尼的耐药性。综上所述，我们的体外数据表明PC-9 / GR细胞下调CYLD表达，增强随后的CYLD依赖性抗凋亡能力和炎症反应，这可能为NSCLC中获得吉非替尼耐药性治疗提供了可能的靶标。沉默CYLD的表达导致白介素-6，转化生长因子-β和肿瘤坏死因子-α的表达水平增加，这可能有助于PC-9细胞对吉非替尼的获得性耐药。综上所述，我们的体外数据表明PC-9 / GR细胞下调CYLD表达，增强随后的CYLD依赖性抗凋亡能力和炎症反应，这可能为NSCLC中获得吉非替尼耐药性治疗提供了可能的靶标。沉默CYLD的表达导致白介素-6，转化生长因子-β和肿瘤坏死因子-α的表达水平增加，这可能有助于PC-9细胞对吉非替尼的获得性耐药。综上所述，我们的体外数据表明PC-9 / GR细胞下调CYLD表达，增强随后的CYLD依赖性抗凋亡能力和炎症反应，这可能为NSCLC中获得吉非替尼耐药性治疗提供了可能的靶标。