Chien Andy J, Haydu Lauren E, Biechele Travis L, Kulikauskas Rima M, Rizos Helen, Kefford Richard F, Scolyer Richard A, Moon Randall T, Long Georgina V
Division of Dermatology, University of Washington Department of Medicine, Seattle, Washington, United States of America; The Group Health Research Institute, Seattle, Washington, United States of America.
Melanoma Institute of Australia, Sydney, New South Wales, Australia; The University of Sydney, Sydney, New South Wales, Australia.
PLoS One. 2014 Apr 14;9(4):e94748. doi: 10.1371/journal.pone.0094748. eCollection 2014.
Unprecedented clinical responses have been reported in advanced stage metastatic melanoma patients treated with targeted inhibitors of constitutively activated mutant BRAF, which is present in approximately half of all melanomas. We and others have previously observed an association of elevated nuclear β-catenin with improved survival in molecularly-unselected melanoma patients. This study sought to determine whether levels of Wnt/β-catenin signaling in melanoma tumors prior to treatment might predict patient responses to BRAF inhibitors (BRAFi). We performed automated quantification of β-catenin immunohistochemical expression in pretreatment BRAF-mutant tumors from 32 BRAFi-treated melanoma patients. Unexpectedly, patients with higher nuclear β-catenin in their tumors did not exhibit the survival advantage previously observed in molecularly-unselected melanoma patients who did not receive BRAFi. In cultured melanoma cells treated with long-term BRAFi, activation of Wnt/β-catenin signaling is markedly inhibited, coinciding with a loss of the enhancement of BRAFi-induced apoptosis by WNT3A observed in BRAFi-naïve cells. Together, these observations suggest that long-term treatment with BRAFi can impact the interaction between BRAF/MAPK and Wnt/β-catenin signaling to affect patient outcomes. Studies with larger patient cohorts are required to determine whether nuclear β-catenin expression correlates with clinical responses to BRAFi and to specific mechanisms of acquired resistance to BRAFi. Understanding these pathway interactions will be necessary to facilitate efforts to individualize therapies for melanoma patients.
据报道，在接受组成型激活突变BRAF靶向抑制剂治疗的晚期转移性黑色素瘤患者中出现了前所未有的临床反应，约一半的黑色素瘤中存在这种突变。我们和其他人之前观察到，在未进行分子筛选的黑色素瘤患者中，核β-连环蛋白水平升高与生存率提高有关。本研究旨在确定治疗前黑色素瘤肿瘤中Wnt/β-连环蛋白信号通路水平是否可预测患者对BRAF抑制剂（BRAFi）的反应。我们对32例接受BRAFi治疗的黑色素瘤患者治疗前BRAF突变肿瘤中的β-连环蛋白免疫组化表达进行了自动定量分析。出乎意料的是，肿瘤中核β-连环蛋白水平较高的患者并未表现出之前在未接受BRAFi的未进行分子筛选的黑色素瘤患者中观察到的生存优势。在用长期BRAFi处理的培养黑色素瘤细胞中，Wnt/β-连环蛋白信号通路的激活受到显著抑制，这与在未接触过BRAFi的细胞中观察到的WNT3A增强BRAFi诱导的凋亡作用的丧失相一致。这些观察结果共同表明，长期使用BRAFi治疗可影响BRAF/MAPK和Wnt/β-连环蛋白信号通路之间的相互作用，从而影响患者的预后。需要对更大的患者队列进行研究，以确定核β-连环蛋白表达是否与对BRAFi的临床反应以及对BRAFi获得性耐药的具体机制相关。了解这些信号通路的相互作用对于促进黑色素瘤患者个体化治疗的努力至关重要。
