Lineage dedifferentiation toward a mesenchymal-like state displaying myofibroblast and fibrotic features is a common mechanism of adaptive and acquired resistance to targeted therapy in melanoma. Here, we show that the anti-fibrotic drug nintedanib is active to normalize the fibrous ECM network, enhance the efficacy of MAPK-targeted therapy, and delay tumor relapse in a preclinical model of melanoma. Acquisition of this resistant phenotype and its reversion by nintedanib pointed to miR-143/-145 pro-fibrotic cluster as a driver of this mesenchymal-like phenotype. Upregulation of the miR-143/-145 cluster under BRAFi/MAPKi therapy was observed in melanoma cells in vitro and in vivo and was associated with an invasive/undifferentiated profile. The 2 mature miRNAs generated from this cluster, miR-143-3p and miR-145-5p, collaborated to mediate transition toward a drug-resistant undifferentiated mesenchymal-like state by targeting Fascin actin-bundling protein 1 (FSCN1), modulating the dynamic crosstalk between the actin cytoskeleton and the ECM through the regulation of focal adhesion dynamics and mechanotransduction pathways. Our study brings insights into a novel miRNA-mediated regulatory network that contributes to non-genetic adaptive drug resistance and provides proof of principle that preventing MAPKi-induced pro-fibrotic stromal response is a viable therapeutic opportunity for patients on targeted therapy.

中文翻译：

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阻断由 miR-143/-145 簇介导的促纤维化反应增强了对黑色素瘤靶向治疗的反应

向显示肌成纤维细胞和纤维化特征的间充质样状态的谱系去分化是黑色素瘤对靶向治疗的适应性和获得性耐药的常见机制。在这里，我们展示了抗纤维化药物 nintedanib 在黑色素瘤的临床前模型中具有使纤维 ECM 网络正常化、增强 MAPK 靶向治疗的功效和延缓肿瘤复发的活性。nintedanib 获得这种耐药表型及其逆转表明 miR-143/-145 促纤维化簇是这种间充质样表型的驱动因素。在体外和体内的黑色素瘤细胞中观察到 BRAFi/MAPKi 治疗下 miR-143/-145 簇的上调并且与侵入性/未分化特征相关。由该簇产生的 2 个成熟 miRNA，miR-143-3p 和 miR-145-5p，通过靶向 Fascin 肌动蛋白捆绑蛋白 1 (FSCN1) 协作介导向耐药性未分化间充质样状态的转变，调节动态通过调节粘着斑动力学和机械转导途径，肌动蛋白细胞骨架和 ECM 之间的串扰。我们的研究带来了对一种新型 miRNA 介导的调节网络的见解，该网络有助于非遗传适应性耐药性，并提供了原理证明，即预防 MAPKi 诱导的促纤维化基质反应对于接受靶向治疗的患者来说是一个可行的治疗机会。