Background: Epidermal growth factor receptor (EGFR)-targeted tyrosine kinase inhibitors (TKIs) have exhibited efficacy in EGFR-mutant non-small cell lung cancer (NSCLC) patients. However, the response is modest in patients with wild-type (wt)-EGFR, and approximately 30–40% of patients develop TKI resistance. Recently, a role for BRG1 (SMARCA4) in regulating gene expression and its frequent alteration in various cancers, including NSCLC, has been reported. Yet, its specific function in response to EGFR-TKI therapy remains elusive. Herein, we investigated the role of BRG1 in EGFR-TKI response in vitro and in vivo using lung cancer models.Methods: In vitro, A549, H358, and HCC827 cell lines that varied in their EGFR and BRG1 status were assessed for response to EGFR-TKI upon overexpression or gene silencing of BRG1 through cell viability, cell migration, and Western blotting assays. In vivo, A549 and H358 tumor xenografts that overexpressed BRG1 or had BRG1 silenced were investigated for tumor growth response to EGFR-TKI.Results: EGFRwt/BRG1mt (A549) cells were resistant to TKI, and restoration of wt-BRG1 expression reverted them to TKI sensitivity both in vitro and in vivo. In contrast, silencing of BRG1wt in H358 cells showed a tendency toward TKI resistance. Additionally, wt-EGFR and pAKTSer473protein complex formation in A549 cells was disrupted with an AKT inhibitor (MK2206), resulting in enhanced cytotoxicity in vitro.Conclusions: Our study demonstrates that EGFR-TKI response in wt-EGFR cells is dictated by BRG1 status. These findings propose screening of wt-EGFR NSCLC patients for BRG1 status for identifying individuals likely to benefit from EGFR-TKI therapy versus patients who will benefit from AKT inhibitor treatment.
背景：表皮生长因子受体（EGFR）靶向酪氨酸激酶抑制剂（TKIs）在EGFR突变的非小细胞肺癌（NSCLC）患者中显示出疗效。然而，在野生型（wt）EGFR患者中反应有限，且约30-40%的患者会产生TKI耐药。近期研究表明，BRG1（SMARCA4）在基因表达调控中发挥作用，并在包括NSCLC在内的多种癌症中频繁发生改变，但其在EGFR-TKI治疗反应中的具体功能尚不明确。本研究通过肺癌模型在体外和体内探讨了BRG1在EGFR-TKI治疗反应中的作用。 方法：在体外实验中，选用具有不同EGFR和BRG1状态的A549、H358和HCC827细胞系，通过细胞活力、细胞迁移和Western blot检测，评估BRG1过表达或基因沉默对EGFR-TKI反应的影响。在体内实验中，研究过表达BRG1或沉默BRG1的A549和H358肿瘤异种移植模型对EGFR-TKI的肿瘤生长反应。 结果：EGFRwt/BRG1mt（A549）细胞对TKI具有耐药性，而恢复wt-BRG1表达可在体外和体内使其恢复TKI敏感性。相反，沉默H358细胞中的BRG1wt则表现出TKI耐药趋势。此外，使用AKT抑制剂（MK2206）可破坏A549细胞中wt-EGFR与pAKTSer473蛋白复合物的形成，从而增强体外细胞毒性。 结论：本研究证实，wt-EGFR细胞对EGFR-TKI的反应取决于BRG1状态。这些发现建议对wt-EGFR NSCLC患者进行BRG1状态筛查，以识别可能从EGFR-TKI治疗中获益的个体，以及可能从AKT抑制剂治疗中获益的患者。
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