Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance.
Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance.
复制标题
作者：
BRAF的突变激活是人类黑色素瘤中最常见的基因改变，≥50%的肿瘤表达BRAF（V600E）癌蛋白。此外，晚期BRAF突变黑色素瘤患者在接受维莫非尼治疗后肿瘤显著消退且生存期延长，这表明致癌性BRAF在黑色素瘤的维持中起着关键作用。然而，由于大多数患者会因耐药性疾病复发且病情致命，了解和预防耐药机制对于提供更好的治疗至关重要。在此，我们利用两个独立衍生的原发性人类黑色素瘤异种移植模型研究维莫非尼耐药的原因和后果，这两个模型通过持续给予维莫非尼来筛选耐药性。在其中一个模型中，由于BRAF（V600E）表达升高，耐药肿瘤显示出对BRAF（V600E）→MEK→ERK信号通路的持续依赖。最重要的是，我们证明维莫非尼耐药的黑色素瘤在持续增殖方面变得依赖药物，因此停止给药会导致已形成的耐药肿瘤消退。我们进一步证明，一种间断给药策略可利用耐药细胞在无药物时表现出的适应性劣势，延缓致命耐药性疾病的发生。这些数据强调了耐药细胞也可能表现出药物依赖性这一概念，因此改变给药方式可能防止致命耐药性的出现。这些观察结果可能有助于维持维莫非尼反应的持久性，最终目标是为BRAF突变的黑色素瘤患者亚群提供治愈性治疗。
Mutational activation of BRAF is the most prevalent genetic alteration in human melanoma, with ≥ 50% of tumours expressing the BRAF(V600E) oncoprotein. Moreover, the marked tumour regression and improved survival of late-stage BRAF-mutated melanoma patients in response to treatment with vemurafenib demonstrates the essential role of oncogenic BRAF in melanoma maintenance. However, as most patients relapse with lethal drug-resistant disease, understanding and preventing mechanism(s) of resistance is critical to providing improved therapy. Here we investigate the cause and consequences of vemurafenib resistance using two independently derived primary human melanoma xeno-graft models in which drugresistanceisselected by continuous vemurafenib administration. In one of these models, resistant tumours show continued dependency on BRAF(V600E) → MEK → ERK signalling owing to elevated BRAF(V600E) expression. Most importantly, we demonstrate that vemurafenib-resistant melanomas become drug dependent for their continued proliferation, such that cessation of drug administration leads to regression of established drug-resistant tumours. We further demonstrate that a discontinuous dosing strategy, which exploits the fitness disadvantage displayed by drug-resistant cells in the absence of the drug, forestalls the onset of lethal drug-resistant disease. These data highlight the concept that drug-resistant cells may also display drug dependency, such that altered dosing may prevent the emergence of lethal drug resistance. Such observations may contribute to sustaining the durability of the vemurafenib response with the ultimate goal of curative therapy for the subset of melanoma patients with BRAF mutations.