The Second Hospital of Dalian Medical University, Dalian, 116023, China.
Guangzhou women and children's medical center, Guangzhou Medical University, Guangzhou, 510623, China.
Respir Res. 2024 May 20;25(1):215. doi: 10.1186/s12931-024-02844-9.
BACKGROUND: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of lung cancer patients with mutated EGFR. However, the efficacy of EGFR-TKIs in wild-type EGFR tumors has been shown to be marginal. Methods that can sensitize EGFR-TKIs to EGFR wild-type NSCLC remain rare. Hence, we determined whether combination treatment can maximize the therapeutic efficacy of EGFR-TKIs. METHODS: We established a focused drug screening system to investigate candidates for overcoming the intrinsic resistance of wild-type EGFR NSCLC to EGFR-TKIs. Molecular docking assays and western blotting were used to identify the binding mode and blocking effect of the candidate compounds. Proliferation assays, analyses of drug interactions, colony formation assays, flow cytometry and nude mice xenograft models were used to determine the effects and investigate the molecular mechanism of the combination treatment. RESULTS: Betulinic acid (BA) is effective at targeting EGFR and synergizes with EGFR-TKIs (gefitinib and osimertinib) preferentially against wild-type EGFR. BA showed inhibitory activity due to its interaction with the ATP-binding pocket of EGFR and dramatically enhanced the suppressive effects of EGFR-TKIs by blocking EGFR and modulating the EGFR-ATK-mTOR axis. Mechanistic studies revealed that the combination strategy activated EGFR-induced autophagic cell death and that the EGFR-AKT-mTOR signaling pathway was essential for completing autophagy and cell cycle arrest. Activation of the mTOR pathway or blockade of autophagy by specific chemical agents markedly attenuated the effect of cell cycle arrest. In vivo administration of the combination treatment caused marked tumor regression in the A549 xenografts. CONCLUSIONS: BA is a potential wild-type EGFR inhibitor that plays a critical role in sensitizing EGFR-TKI activity. BA combined with an EGFR-TKI effectively suppressed the proliferation and survival of intrinsically resistant lung cancer cells via the inhibition of EGFR as well as the induction of autophagy-related cell death, indicating that BA combined with an EGFR-TKI may be a potential therapeutic strategy for overcoming the primary resistance of wild-type EGFR-positive lung cancers.
背景：表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKIs）改变了 EGFR 突变型肺癌患者的治疗方式。然而，EGFR-TKIs 对 EGFR 野生型肿瘤的疗效已被证明微不足道。能够使 EGFR-TKIs 对 EGFR 野生型非小细胞肺癌（NSCLC）敏感的方法仍然很少见。因此，我们确定联合治疗是否可以最大程度地提高 EGFR-TKIs 的治疗效果。
方法：我们建立了一个集中药物筛选系统，以研究克服 EGFR-TKIs 对 EGFR 野生型 NSCLC 固有耐药性的候选药物。分子对接实验和 Western blot 用于鉴定候选化合物的结合模式和阻断作用。增殖实验、药物相互作用分析、集落形成实验、流式细胞术和裸鼠异种移植模型用于确定联合治疗的效果并研究其分子机制。
结果：白桦脂酸（BA）能有效靶向 EGFR，并与 EGFR-TKIs（吉非替尼和奥希替尼）协同作用，优先针对野生型 EGFR。BA 通过与 EGFR 的 ATP 结合口袋相互作用，显著增强 EGFR-TKIs 的抑制作用，从而阻断 EGFR 并调节 EGFR-ATK-mTOR 轴，显示出抑制活性。机制研究表明，联合策略激活了 EGFR 诱导的自噬细胞死亡，EGFR-AKT-mTOR 信号通路对于完成自噬和细胞周期阻滞是必不可少的。mTOR 通路的激活或通过特异性化学试剂阻断自噬显著减弱了细胞周期阻滞的作用。体内给予联合治疗导致 A549 异种移植瘤明显消退。
结论：BA 是一种潜在的 EGFR 野生型抑制剂，在增强 EGFR-TKI 活性方面发挥着关键作用。BA 与 EGFR-TKI 联合有效抑制了内在耐药性肺癌细胞的增殖和存活，其机制既通过抑制 EGFR，又通过诱导自噬相关的细胞死亡。这表明 BA 联合 EGFR-TKI 可能是克服 EGFR 阳性野生型 NSCLC 原发性耐药的一种潜在治疗策略。
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