Increased MAPK reactivation in early resistance to dabrafenib/trametinib combination therapy of BRAF-mutant metastatic melanoma
Increased MAPK reactivation in early resistance to dabrafenib/trametinib combination therapy of BRAF-mutant metastatic melanoma
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DOI：
10.1038/ncomms6694
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发表时间：
2014-12-01
影响因子：
16.6
通讯作者：
Rizos, Helen
中科院分区：
文献类型：
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作者：
Long, Georgina V.;Fung, Carina;Rizos, Helen
三分之一的BRAF突变转移性黑色素瘤患者接受联合BRAF和MEK抑制治疗，在6个月内进展。这些患者的治疗选择仍然有限。在这里，我们分析了20 BRAF（V600）突变的黑色素瘤转移来自10例患者的联合治疗达拉非尼和曲美替尼的耐药机制和遗传相关的反应。在9/11例进展性肿瘤中鉴定出耐药机制，并且在9/10例肿瘤中发生MAPK再活化，通常通过BRAF扩增和激活NRAS和MEK 2的突变。我们的数据证实，MEK 2（C125 S），而不是同义的MEK 1（C121 S）蛋白，赋予耐药的联合治疗突出了这些激酶之间的功能差异和MEK 2突变的优势，在联合治疗耐药的黑色素瘤。外显子组测序未发现其他进展特异性耐药候选者。然而，大多数黑色素瘤在基线时携带额外的致癌突变（例如，RAC 1和AKT 3），这些突变激活MAPK和PI 3 K通路，因此预计会减少对MAPK抑制剂的反应。
One-third of BRAF-mutant metastatic melanoma patients treated with combined BRAF and MEK inhibition progress within 6 months. Treatment options for these patients remain limited. Here we analyse 20 BRAF(V600)-mutant melanoma metastases derived from 10 patients treated with the combination of dabrafenib and trametinib for resistance mechanisms and genetic correlates of response. Resistance mechanisms are identified in 9/11 progressing tumours and MAPK reactivation occurred in 9/10 tumours, commonly via BRAF amplification and mutations activating NRAS and MEK2. Our data confirming that MEK2(C125S), but not the synonymous MEK1(C121S) protein, confers resistance to combination therapy highlight the functional differences between these kinases and the preponderance of MEK2 mutations in combination therapy-resistant melanomas. Exome sequencing did not identify additional progression-specific resistance candidates. Nevertheless, most melanomas carried additional oncogenic mutations at baseline (for example, RAC1 and AKT3) that activate the MAPK and PI3K pathways and are thus predicted to diminish response to MAPK inhibitors.