Department of Respiratory and Infectious Disease of Geriatrics, The First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang 110001, China.
Department of Respiratory and Infectious Disease of Geriatrics, The First Hospital of China Medical University, Shenyang 110001, China; Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang 110001, China; Department of Oncology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121001, China.
Pharmacol Res. 2020 Sep;159:105007. doi: 10.1016/j.phrs.2020.105007. Epub 2020 Jun 17.
Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) were first-line treatments for NSCLC patients with EGFR-mutations. However, about 30 % of responders relapsed within six months because of acquired resistance. In this study, we used Connectivity Map (CMap) to discover a drug capable of reversing acquired EGFR-TKIs resistance. To investigate Lymecycline's ability to reverse acquired EGFR-TKIs resistance, two Icotinib resistant cell lines were constructed. Lymecycline's ability to suppress the proliferation of Icotinib resistant cells in vitro and in vivo was then evaluated. Molecular targets were predicted using network pharmacology and used to identify the molecular mechanism. Growth factor receptor-bound protein 2 (GRB2) is an EGFR-binding adaptor protein essential for EGFR phosphorylation and regulation of AKT/ERK/STAT3 signaling pathways. Lymecycline targeted GRB2 and inhibited the resistance of the cell cycle to EGFR-TKI, arresting disease progression and inducing apoptosis in cancer cells. Combined Lymecycline and Icotinib treatment produced a synergistic effect and induced apoptosis in HCC827R5 and PC9R10 cells. Cell proliferation in resistant cancer cells was significantly inhibited by the combined Lymecycline and Icotinib treatment in mouse models. Lymecycline inhibited the resistance of the cell cycle to EGFR-TKI and induced apoptosis in NSCLC by inhibiting EGFR phosphorylation and GRB2-mediated AKT/ERK/STAT3 signaling pathways. This provided strong support that Lymecycline when combined with EGFR targeting drugs, enhanced the efficacy of treatments for drug-resistant NSCLC.
表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）是 EGFR 突变的 NSCLC 患者的一线治疗药物。然而，约 30%的应答者在六个月内因获得性耐药而复发。在这项研究中，我们使用连接图谱（CMap）来发现一种能够逆转获得性 EGFR-TKI 耐药的药物。为了研究林可霉素逆转获得性 EGFR-TKI 耐药的能力，构建了两个厄洛替尼耐药细胞系。然后评估林可霉素抑制厄洛替尼耐药细胞在体外和体内增殖的能力。使用网络药理学预测分子靶标，并用于鉴定分子机制。生长因子受体结合蛋白 2（GRB2）是 EGFR 结合衔接蛋白，对 EGFR 磷酸化和 AKT/ERK/STAT3 信号通路的调节至关重要。林可霉素靶向 GRB2 并抑制 EGFR-TKI 的耐药性，阻止疾病进展并诱导癌细胞凋亡。林可霉素和厄洛替尼联合治疗产生协同作用，并诱导 HCC827R5 和 PC9R10 细胞凋亡。在耐药性癌细胞中，林可霉素和厄洛替尼联合治疗显著抑制细胞增殖。林可霉素通过抑制 EGFR 磷酸化和 GRB2 介导的 AKT/ERK/STAT3 信号通路，抑制 EGFR-TKI 的耐药性并诱导 NSCLC 细胞凋亡。这为林可霉素与 EGFR 靶向药物联合使用增强耐药性 NSCLC 治疗效果提供了有力支持。
