The echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion gene occurs in approximately 5% of non-small-cell lung cancers (NSCLCs). The development of ALK tyrosine kinase inhibitors (ALK-TKIs) is a major advance in treating NSCLC with the ALK fusion gene. Nevertheless, acquired resistance to ALK-TKIs ultimately limits their use. A prevalent mechanism of drug resistance in kinases occurs through the mutation of G1202R in ALK. However, the mechanisms underlying G1202R resistance to ceritinib are not fully understood. Here, we demonstrated that the expression of EML4-ALK G1202R mutation in A549 cells induced an epithelial-mesenchymal transition (EMT) phenotype and significantly increased the migration and invasion abilities. These phenomena may be due to the upregulation of signal transducer and activator of transcription 3 (STAT3), accompanied by the elevated expression of Slug in EML4-ALK G1202R mutant cells. Furthermore, the combination of ALK and STAT3 inhibitors restored the sensitivity of EML4-ALK G1202R mutant cells to ceritinib. In conclusion, these data indicate that the EML4-ALK G1202R mutation mediates the EMT phenotype by activating the STAT3/Slug signaling pathway, resulting in resistance to ceritinib, and that the combination of STAT3 and ALK inhibitors may overcome ALK mutation-driven drug resistance in the clinic.

棘皮动物微管相关蛋白样 4 (EML4)-间变性淋巴瘤激酶 (ALK) 融合基因发生在大约 5% 的非小细胞肺癌 (NSCLC) 中。ALK 酪氨酸激酶抑制剂 (ALK-TKI) 的开发是使用 ALK 融合基因治疗 NSCLC 的重大进展。然而，对 ALK-TKI 的获得性耐药最终限制了它们的使用。激酶中耐药性的普遍机制是通过 ALK 中 G1202R 的突变发生的。然而，G1202R 对色瑞替尼耐药的机制尚不完全清楚。在这里，我们证明了 EML4-ALK G1202R 突变在 A549 细胞中的表达诱导了上皮间质转化 (EMT) 表型并显着增加了迁移和侵袭能力。这些现象可能是由于信号转导和转录激活因子 3 (STAT3) 的上调，伴随着 EML4-ALK G1202R 突变细胞中 Slug 的表达升高。此外，ALK 和 STAT3 抑制剂的组合恢复了 EML4-ALK G1202R 突变细胞对色瑞替尼的敏感性。总之，这些数据表明 EML4-ALK G1202R 突变通过激活 STAT3/Slug 信号通路介导 EMT 表型，导致对色瑞替尼产生耐药性，并且 STAT3 和 ALK 抑制剂的组合可以克服 ALK 突变驱动的耐药性。诊所。