Anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) have improved clinical outcomes in non-small cell lung cancer (NSCLC) harboring ALK- rearrangements. However, a small population of tumor cells survives due to adaptive resistance under drug pressure and ultimately acquires drug resistance. Thus, it is necessary to elucidate the mechanisms underlying the prevention of drug resistance to improve the prognosis of patients with ALK-rearranged NSCLC. We identified novel adaptive resistance, generated through c-Jun N-terminal kinase (JNK)/c-Jun signaling, to initial ALK-TKIs—alectinib and brigatinib—in ALK-rearranged NSCLC. Inhibition of JNK/c-Jun axis showed suppression of growth and promotion of apoptosis induced by ALK-TKIs in drug-tolerant cells. JNK inhibition, in combination with the use of ALK-TKIs, increased cell apoptosis through repression of the Bcl-xL proteins, compared with ALK-TKI monotherapy. Importantly, combination therapy targeting JNK and ALK significantly delayed the regrowth following cessation of these treatments. Together, our results demonstrated that JNK pathway activation plays a pivotal role in the intrinsic resistance to ALK-TKIs and the emergence of ALK-TKI-tolerant cells in ALK-rearranged NSCLC, thus indicating that optimal inhibition of tolerant signals combined with ALK-TKIs may potentially improve the outcome of ALK-rearranged NSCLC.

间变性淋巴瘤激酶-酪氨酸激酶抑制剂 (ALK-TKI) 改善了携带ALK重排的非小细胞肺癌 (NSCLC) 的临床结果。然而，一小部分肿瘤细胞由于在药物压力下的适应性耐药而存活并最终获得耐药性。因此，有必要阐明预防耐药性的潜在机制，以改善ALK重排 NSCLC患者的预后。我们确定了新的自适应电阻，通过C-Jun N-末端激酶（JNK）/ c-Jun的信令，到初始ALK-的TKI-alectinib和brigatinib-在生成ALK-重排非小细胞肺癌。JNK/c-Jun 轴的抑制表明 ALK-TKI 在耐药细胞中诱导的生长受到抑制和细胞凋亡的促进。与 ALK-TKI 单一疗法相比，JNK 抑制与 ALK-TKI 联合使用可通过抑制 Bcl-xL 蛋白增加细胞凋亡。重要的是，针对 JNK 和 ALK 的联合治疗显着延迟了这些治疗停止后的再生。总之，我们的结果表明，JNK途径活化在到ALK-TKI中的固有电阻关键作用和ALK-TKI耐受细胞中的出现ALK -rearranged NSCLC，从而指示与ALK-TKI的组合宽容信号的该最佳抑制可能潜在地改善ALK重排 NSCLC的结果。