Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong, 510095, China.
Guangzhou Institute of Cardiovascular Disease, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510260, China.
Eur J Pharmacol. 2019 Aug 5;856:172409. doi: 10.1016/j.ejphar.2019.172409. Epub 2019 May 25.
EGF receptor tyrosine kinase inhibitors (EGFR-TKIs) have been widely used as a standard therapy in non-small cell lung cancer (NSCLC) patients with EGFR mutations. However, most if not all of the patients who initially have responded to EGFR-TKIs later experience progression or deterioration of the disease while still on the treatment. Drug resistance becomes inevitable due to the emergence of the second-site EGFR T790M mutation within exon 20, MET and HER2 amplification, small cell histologic transformation and rare secondary BRAF mutations. The acquired drug resistance limits the efficacy of EGFR-TKIs in patients. Thalidomide is a widely used anti-angiogenic and immunomodulatory drug with anticancer effects. The current study was aimed to explore the combined effects of gefitinib and thalidomide on NSCLC. The combination of thalidomide and gefitinib induced antiproliferative and proapoptotic effects in HCC827, PC9, and PC9GR cells. The inhibition of EGFR phosphorylation and downstream signaling was more pronounced in the thalidomide and gefitinib co-treatment group as compared with the single agent treatment groups. Further study revealed that the inhibitors of AKT, MEK/ERK, and p38 increased the antiproliferative and proapoptotic effects of the combined treatment of thalidomide and gefitinib. However, JNK inhibition moderately abrogated cell apoptosis induced by the co-treatment. In conclusion, thalidomide and gefitinib exhibit synergistic effects on both TKI-sensitive and -resistant NSCLC cells by targeting the EGFR signaling pathways, suggesting that the combination strategy is promising for the treatment of NSCLC.
表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs）已广泛应用于具有 EGFR 突变的非小细胞肺癌（NSCLC）患者的标准治疗中。然而，大多数（如果不是全部）最初对 EGFR-TKIs 有反应的患者在治疗过程中仍会出现疾病进展或恶化。由于第二部位 EGFR T790M 突变、MET 和 HER2 扩增、小细胞组织学转化和罕见的继发性 BRAF 突变的出现，药物耐药性不可避免。获得性耐药性限制了 EGFR-TKIs 在患者中的疗效。沙利度胺是一种广泛使用的抗血管生成和免疫调节药物，具有抗癌作用。本研究旨在探讨吉非替尼和沙利度胺联合应用于 NSCLC 的效果。沙利度胺和吉非替尼联合作用于 HCC827、PC9 和 PC9GR 细胞，诱导细胞增殖抑制和促凋亡作用。与单药治疗组相比，沙利度胺和吉非替尼联合治疗组 EGFR 磷酸化和下游信号通路的抑制作用更为明显。进一步的研究表明，AKT、MEK/ERK 和 p38 的抑制剂增加了沙利度胺和吉非替尼联合治疗的抗增殖和促凋亡作用。然而，JNK 抑制剂中度削弱了联合治疗诱导的细胞凋亡。总之，沙利度胺和吉非替尼通过靶向 EGFR 信号通路对 TKI 敏感和耐药的 NSCLC 细胞均表现出协同作用，提示联合治疗策略有望用于 NSCLC 的治疗。
