Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy.
Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy.
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DOI：
10.1158/2159-8290.cd-13-0642
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发表时间：
2014-01
期刊：
影响因子：
28.2
通讯作者：
Lo RS
中科院分区：
文献类型：
--
作者：
Shi H;Hugo W;Kong X;Hong A;Koya RC;Moriceau G;Chodon T;Guo R;Johnson DB;Dahlman KB;Kelley MC;Kefford RF;Chmielowski B;Glaspy JA;Sosman JA;van Baren N;Long GV;Ribas A;Lo RS
在大多数V600BRAF突变黑色素瘤患者中，BRAF抑制剂能引起快速的抗肿瘤反应，但获得性耐药性几乎是普遍存在的。我们试图确定疾病进展过程中的核心耐药途径和肿瘤异质性的程度。我们发现，在70%的疾病进展组织中检测到MAPK重新激活机制，其中RAS突变、突变的BRAF扩增和选择性剪接是最常见的。我们还在22%的进行性黑色素瘤中检测到PI3K-PTEN-AKT-上调的基因改变。在两个核心药物逃逸途径中，不同的分子损伤通常同时在同一肿瘤中或同一患者的多个肿瘤中被检测到。除了具有广泛的异质性耐药机制外，从BRAF抑制剂选择中出现的黑色素瘤再生长显示出分支进化，其特征是突变光谱/特征改变和适合性增加。因此，黑色素瘤基因组的异质性是导致BRAF抑制剂治疗失败的重要原因，这意味着预先将两条核心通路作为持久反应的基本策略。
BRAF inhibitors elicit rapid anti-tumor responses in the majority of patients with V600BRAF mutant melanoma, but acquired drug resistance is almost universal. We sought to identify the core resistance pathways and the extent of tumor heterogeneity during disease progression. We show that MAPK reactivation mechanisms were detected among 70% of disease-progressive tissues, with RAS mutations, mutant BRAF amplification and alternative splicing being most common. We also detected PI3K-PTEN-AKT-upregulating genetic alterations among 22% of progressive melanomas. Distinct molecular lesions, in both core drug escape pathways, were commonly detected concurrently in the same tumor or among multiple tumors from the same patient. Beyond harboring extensively heterogeneous resistance mechanisms, melanoma re-growth emerging from BRAF inhibitor selection displayed branched evolution marked by altered mutational spectra/signatures and increased fitness. Thus, melanoma genomic heterogeneity contributes significantly to BRAF inhibitor treatment failure, implying upfront, co-targeting of two core pathways as an essential strategy for durable responses.