Abstract：
Acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) represents a primary cause of treatment failure in non-small cell lung cancer (NSCLC) patients. Chemokine (C-C motif) ligand 2 (CCL2) is recently found to play a pivotal role in determining anti-cancer treatment response. However, the role and mechanism of CCL2 in the development of EGFR-TKIs resistance have not been fully elucidated. In the present study, we focus on the function of CCL2 in the development of acquired resistance to EGFR-TKIs in NSCLC cells. Our results show that CCL2 is aberrantly upregulated in EGFR-TKIs-resistant NSCLC cells and that CCL2 overexpression significantly diminishes sensitivity to EGFR-TKIs. Conversely, CCL2 suppression by CCL2 synthesis inhibitor, bindarit, or CCL2 knockdown can reverse this resistance. CCL2 upregulation can also lead to enhanced migration and increased expressions of epithelial-mesenchymal transition (EMT) markers in EGFR-TKI-resistant NSCLC cells, which could also be rescued by CCL2 knockdown or inhibition. Furthermore, our findings suggest that CCL2-dependent EGFR-TKIs resistance involves the AKT-EMT signaling pathway; inhibition of this pathway effectively attenuates CCL2-induced cell migration and EMT marker expression. In summary, CCL2 promotes the development of acquired EGFR-TKIs resistance and EMT while activating AKT signaling in NSCLC. These insights suggest a promising avenue for the development of CCL2-targeted therapies that prevent EGFR-TKIs resistance in NSCLC.
摘要：
对EGFR酪氨酸激酶抑制剂（EGFR-TKIs）的获得性耐药是非小细胞肺癌（NSCLC）患者治疗失败的主要原因。最近发现趋化因子（C-C基序）配体2（CCL2）在确定抗癌治疗反应中起关键作用。然而,CCL2在EGFR-TKIs耐药中的作用和机制尚未完全阐明.在本研究中,我们关注CCL2在NSCLC细胞EGFR-TKIs获得性耐药发展中的作用。我们的结果表明，CCL2在EGFR-TKIs耐药的NSCLC细胞中异常上调，CCL2过表达显着降低了对EGFR-TKIs的敏感性。相反，CCL2合成抑制剂抑制CCL2，bindarit,或CCL2敲低可以逆转这种阻力。CCL2上调还可导致EGFR-TKI耐药NSCLC细胞的迁移增强和上皮间质转化（EMT）标志物表达增加，也可以通过CCL2敲低或抑制来挽救。此外，我们的研究结果表明,CCL2依赖性EGFR-TKIs耐药涉及AKT-EMT信号通路;抑制该通路可有效减弱CCL2诱导的细胞迁移和EMT标志物表达.总之,CCL2促进获得性EGFR-TKIs耐药性和EMT的发展，同时激活NSCLC中的AKT信号传导。这些见解为开发CCL2靶向疗法提供了一个有希望的途径，该疗法可预防NSCLC中的EGFR-TKIs耐药。
