Recovery of phospho-ERK activity allows melanoma cells to escape from BRAF inhibitor therapy.
Recovery of phospho-ERK activity allows melanoma cells to escape from BRAF inhibitor therapy.
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DOI：
10.1038/sj.bjc.6605714
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发表时间：
2010-06-08
影响因子：
8.8
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中科院分区：
文献类型：
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对BRAF抑制剂的耐药性是黑色素瘤领域的一个新问题。迫切需要预防和克服耐药性的战略。使用流式细胞术和western blot检测BRAF抑制后细胞信号传导、BrdU掺入和细胞周期进入的动态。通过细胞凋亡和集落形成实验以及3D器官型细胞培养，证实了BRAF/MEK联合抑制抗药的能力。BRAF抑制导致磷酸化erk （pERK）信号的快速恢复。尽管大多数细胞在药物作用下仍保持生长停滞，但少数细胞保留了其增殖潜力，并逃脱了BRAF抑制剂的治疗。通过联合BRAF/MEK抑制提高细胞凋亡水平和消除耐药性的能力，证明了pERK信号在治疗逃逸中的作用。BRAF/MEK联合抑制可能是防止BRAF- v600e突变黑色素瘤耐药出现的一种策略。
Resistance to BRAF inhibitors is an emerging problem in the melanoma field. Strategies to prevent and overcome resistance are urgently required. The dynamics of cell signalling, BrdU incorporation and cell-cycle entry after BRAF inhibition was measured using flow cytometry and western blot. The ability of combined BRAF/MEK inhibition to prevent the emergence of resistance was demonstrated by apoptosis and colony formation assays and in 3D organotypic cell culture. BRAF inhibition led to a rapid recovery of phospho-ERK (pERK) signalling. Although most of the cells remained growth arrested in the presence of drug, a minor population of cells retained their proliferative potential and escaped from BRAF inhibitor therapy. A function for the rebound pERK signalling in therapy escape was demonstrated by the ability of combined BRAF/MEK inhibition to enhance the levels of apoptosis and abrogate the onset of resistance. Combined BRAF/MEK inhibition may be one strategy to prevent the emergence of drug resistance in BRAF-V600E-mutated melanomas.