Targeted therapy with BRAF and MEK inhibitors has improved the survival of patients with BRAF-mutated metastatic melanoma, but most patients relapse upon the onset of drug resistance induced by mechanisms including genetic and epigenetic events. Among the epigenetic alterations, microRNA perturbation is associated with the development of kinase inhibitor resistance. Here, we identified and studied the role of miR-146a-5p dysregulation in melanoma drug resistance. The miR-146a-5p-regulated NFkB signaling network was identified in drug-resistant cell lines and melanoma tumor samples by expression profiling and knock-in and knock-out studies. A bioinformatic data analysis identified COX2 as a central gene regulated by miR-146a-5p and NFkB. The effects of miR-146a-5p/COX2 manipulation were studied in vitro in cell lines and with 3D cultures of treatment-resistant tumor explants from patients progressing during therapy. miR-146a-5p expression was inversely correlated with drug sensitivity and COX2 expression and was reduced in BRAF and MEK inhibitor-resistant melanoma cells and tissues. Forced miR-146a-5p expression reduced COX2 activity and significantly increased drug sensitivity by hampering prosurvival NFkB signaling, leading to reduced proliferation and enhanced apoptosis. Similar effects were obtained by inhibiting COX2 by celecoxib, a clinically approved COX2 inhibitor. Deregulation of the miR-146a-5p/COX2 axis occurs in the development of melanoma resistance to targeted drugs in melanoma patients. This finding reveals novel targets for more effective combination treatment.

中文翻译：

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miR-146a-5p 通过靶向 COX2 和调节 NFkB 介导的炎症介质来削弱黑色素瘤对激酶抑制剂的抗性。

BRAF 和 MEK 抑制剂的靶向治疗提高了 BRAF 突变的转移性黑色素瘤患者的生存率，但大多数患者在由遗传和表观遗传事件等机制诱导的耐药性发作后复发。在表观遗传改变中，microRNA 扰动与激酶抑制剂抗性的发展有关。在这里，我们确定并研究了 miR-146a-5p 失调在黑色素瘤耐药性中的作用。通过表达谱和敲入和敲除研究，在耐药细胞系和黑色素瘤肿瘤样本中鉴定了 miR-146a-5p 调节的 NFkB 信号网络。生物信息学数据分析确定 COX2 是受 miR-146a-5p 和 NFkB 调节的中心基因。在体外细胞系中研究了 miR-146a-5p/COX2 操作的效果，并使用来自治疗期间进展的患者的治疗抗性肿瘤外植体的 3D 培养物进行了研究。miR-146a-5p 表达与药物敏感性和 COX2 表达负相关，并且在 BRAF 和 MEK 抑制剂耐药的黑色素瘤细胞和组织中降低。强制 miR-146a-5p 表达通过阻碍促存活 NFkB 信号传导降低 COX2 活性并显着增加药物敏感性，导致增殖减少和细胞凋亡增强。塞来昔布（一种临床批准的 COX2 抑制剂）通过抑制 COX2 获得了类似的效果。miR-146a-5p/COX2 轴的失调发生在黑色素瘤患者对靶向药物产生耐药性的过程中。这一发现揭示了更有效联合治疗的新靶点。miR-146a-5p 表达与药物敏感性和 COX2 表达负相关，并且在 BRAF 和 MEK 抑制剂耐药的黑色素瘤细胞和组织中降低。强制 miR-146a-5p 表达通过阻碍促存活 NFkB 信号传导降低 COX2 活性并显着增加药物敏感性，导致增殖减少和细胞凋亡增强。塞来昔布（一种临床批准的 COX2 抑制剂）通过抑制 COX2 获得了类似的效果。miR-146a-5p/COX2 轴的失调发生在黑色素瘤患者对靶向药物产生耐药性的过程中。这一发现揭示了更有效联合治疗的新靶点。miR-146a-5p 表达与药物敏感性和 COX2 表达负相关，并且在 BRAF 和 MEK 抑制剂耐药的黑色素瘤细胞和组织中降低。强制 miR-146a-5p 表达通过阻碍促存活 NFkB 信号传导降低 COX2 活性并显着增加药物敏感性，导致增殖减少和细胞凋亡增强。塞来昔布（一种临床批准的 COX2 抑制剂）通过抑制 COX2 获得了类似的效果。miR-146a-5p/COX2 轴的失调发生在黑色素瘤患者对靶向药物产生耐药性的过程中。这一发现揭示了更有效联合治疗的新靶点。强制 miR-146a-5p 表达通过阻碍促存活 NFkB 信号传导降低 COX2 活性并显着增加药物敏感性，导致增殖减少和细胞凋亡增强。塞来昔布（一种临床批准的 COX2 抑制剂）通过抑制 COX2 获得了类似的效果。miR-146a-5p/COX2 轴的失调发生在黑色素瘤患者对靶向药物产生耐药性的过程中。这一发现揭示了更有效联合治疗的新靶点。强制 miR-146a-5p 表达通过阻碍促存活 NFkB 信号传导降低 COX2 活性并显着增加药物敏感性，导致增殖减少和细胞凋亡增强。塞来昔布（一种临床批准的 COX2 抑制剂）通过抑制 COX2 获得了类似的效果。miR-146a-5p/COX2 轴的失调发生在黑色素瘤患者对靶向药物产生耐药性的过程中。这一发现揭示了更有效联合治疗的新靶点。miR-146a-5p/COX2 轴的失调发生在黑色素瘤患者对靶向药物产生耐药性的过程中。这一发现揭示了更有效联合治疗的新靶点。miR-146a-5p/COX2 轴的失调发生在黑色素瘤患者对靶向药物产生耐药性的过程中。这一发现揭示了更有效联合治疗的新靶点。