Rho-mediated signaling promotes BRAF inhibitor resistance in de-differentiated melanoma cells
Rho-mediated signaling promotes BRAF inhibitor resistance in de-differentiated melanoma cells
复制标题
DOI：
10.1038/s41388-019-1074-1
复制
发表时间：
2020-02-01
期刊：
影响因子：
8
通讯作者：
Neubig, R. R.
中科院分区：
文献类型：
--
作者：
Misek, S. A.;Appleton, K. M.;Neubig, R. R.
超过一半的皮肤黑色素瘤肿瘤具有BRAF（V600 E/K）突变。对BRAF抑制剂（BRAFi）的获得性耐药性仍然是获得持久治疗反应的主要障碍。在这项研究中，我们证明了50-60%的体外获得的维罗非尼耐药的黑色素瘤细胞系显示出RhoA家族GTP酶的活化。在BRAFi抗性黑色素瘤细胞系和肿瘤中，RhoA的活化与黑素细胞谱系基因的表达降低相关。使用机器学习方法，我们建立了基于基因表达的模型来预测265种常见抗癌化合物的药物敏感性。然后，我们将这些特征投射到TCGA皮肤黑色素瘤的集合上，发现低分化肿瘤被预测对多种Rho激酶（ROCK）抑制剂具有增加的敏感性。Rho下游的两个转录效应子MRTF和YAP 1在Rho（高）BRAFi抗性细胞系中被激活，并且抗性细胞对这些转录机制的抑制更敏感。总之，这些结果支持靶向Rho调节的基因转录途径的概念，作为一种有前途的治疗方法，以恢复对BRAFi耐药肿瘤的敏感性，或作为一种联合疗法，以防止耐药性的发生。
Over half of cutaneous melanoma tumors have BRAF(V600E/K) mutations. Acquired resistance to BRAF inhibitors (BRAFi) remains a major hurdle in attaining durable therapeutic responses. In this study we demonstrate that 50-60% of melanoma cell lines with vemurafenib resistance acquired in vitro show activation of RhoA family GTPases. In BRAFi-resistant melanoma cell lines and tumors, activation of RhoA is correlated with decreased expression of melanocyte lineage genes. Using a machine learning approach, we built gene expression-based models to predict drug sensitivity for 265 common anticancer compounds. We then projected these signatures onto the collection of TCGA cutaneous melanoma and found that poorly differentiated tumors were predicted to have increased sensitivity to multiple Rho kinase (ROCK) inhibitors. Two transcriptional effectors downstream of Rho, MRTF and YAP1, are activated in the Rho(High) BRAFi-resistant cell lines, and resistant cells are more sensitive to inhibition of these transcriptional mechanisms. Taken together, these results support the concept of targeting Rho-regulated gene transcription pathways as a promising therapeutic approach to restore sensitivity to BRAFi-resistant tumors or as a combination therapy to prevent the onset of drug resistance.