The c-Jun/RHOB/AKT pathway confers resistance of BRAF-mutant melanoma cells to MAPK inhibitors.
The c-Jun/RHOB/AKT pathway confers resistance of BRAF-mutant melanoma cells to MAPK inhibitors.
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DOI：
10.18632/oncotarget.3888
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发表时间：
2015-06-20
期刊：
影响因子：
--
通讯作者：
Favre G
中科院分区：
文献类型：
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作者：
Delmas A;Cherier J;Pohorecka M;Medale-Giamarchi C;Meyer N;Casanova A;Sordet O;Lamant L;Savina A;Pradines A;Favre G
BRAF突变型黑色素瘤患者对BRAF抑制剂的反应因继发性耐药和快速复发而显著受损。到目前为止，驱动这些抗性的分子机制尚未完全了解。在这里，我们表明，在BRAF突变的黑色素瘤细胞，抑制BRAF或其靶向MEK诱导RHOB的表达的机制，依赖于转录因子c-Jun。在这些细胞中，RHOB缺乏引起超敏反应BRAF和MEK的受体诱导的细胞凋亡。支持这些结果的是，转移性黑色素瘤组织中RHOB表达的丧失与接受维罗非尼治疗的BRAF突变患者的无进展生存期增加相关。在BRAF抑制后，RHOB激活AKT，其抑制引起BRAF突变型黑素瘤细胞对BRAF抑制剂的超敏反应。在小鼠中，AKT抑制与维罗非尼协同作用，以阻断BRAF突变型转移性黑色素瘤的肿瘤生长。我们的研究结果表明，BRAF抑制激活c-Jun/RHOB/AKT通路，促进肿瘤细胞存活，并进一步支持该通路在黑色素瘤对vemurafenib耐药性中的作用。我们的数据还强调了使用RHOB肿瘤水平作为生物标志物来预测vemurafenib患者的反应并选择那些将受益于与AKT抑制剂组合的患者的重要性。
The response of BRAF-mutant melanoma patients to BRAF inhibitors is dramatically impaired by secondary resistances and rapid relapse. So far, the molecular mechanisms driving these resistances are not completely understood. Here, we show that, in BRAF-mutant melanoma cells, inhibition of BRAF or its target MEK induces RHOB expression by a mechanism that depends on the transcription factor c-Jun. In those cells, RHOB deficiency causes hypersensitivity to BRAF and MEK inhibitors-induced apoptosis. Supporting these results, loss of RHOB expression in metastatic melanoma tissues is associated with an increased progression-free survival of BRAF-mutant patients treated with vemurafenib. Following BRAF inhibition, RHOB activates AKT whose inhibition causes hypersensitivity of BRAF-mutant melanoma cells to BRAF inhibitors. In mice, AKT inhibition synergizes with vemurafenib to block tumor growth of BRAF-mutant metastatic melanoma. Our findings reveal that BRAF inhibition activates a c-Jun/RHOB/AKT pathway that promotes tumor cell survival and further support a role of this pathway in the resistance of melanoma to vemurafenib. Our data also highlight the importance of using RHOB tumor levels as a biomarker to predict vemurafenib patient's response and to select those that would benefit of the combination with AKT inhibitors.