Department of Biochemistry, Vanderbilt University, Nashville, Tennessee.
Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
Mol Cancer Res. 2019 Sep;17(9):1842-1853. doi: 10.1158/1541-7786.MCR-19-0257. Epub 2019 Jun 11.
Melanomas are characterized by driver and loss-of-function mutations that promote mitogen-activated protein kinase (MAPK) signaling. MEK inhibitors are approved for use in BRAF-mutated melanoma; however, early-phase clinical trials show occasional responses in driver-negative melanoma, suggesting other alterations conferring MAPK/ERK dependency. To identify additional structural alterations in melanoma, we evaluated RNA-Seq from a set of known MAPK/ERK regulators using a novel population-based algorithm in The Cancer Genome Atlas (TCGA). We identified recurrent MAP3K8 rearrangements in 1.7% of melanomas in TCGA, occurring in more than 15% of tumors without known driver mutations (, and ). Using an independent tumor set, we validated a similar rearrangement frequency by FISH. MAP3K8-rearranged melanomas exhibit a low mutational burden and absence of typical UV-mutational patterns. We identified two melanoma cell lines that harbor endogenous truncating MAP3K8 rearrangements that demonstrate exquisite dependency. Rearrangement and amplification of the MAP3K8 locus in melanoma cells result in increased levels of a truncated, active MAP3K8 protein; oncogenic dependency on the aberrant MAP3K8; and a concomitant resistance to BRAF inhibition and sensitivity to MEK or ERK1/2 inhibition. Our findings reveal and biochemically characterize targetable oncogenic MAP3K8 truncating rearrangements in driver mutation-negative melanoma, and provide insight to therapeutic approaches for patients with these tumors. These data provide rationale for using MEK or ERK inhibitors in a subset of driver-negative, MAPK/ERK-dependent melanomas harboring truncating MAP3K8 rearrangements. IMPLICATIONS: This is the first mechanistic study and therapeutic implications of truncating MAP3K8 rearrangements in driver-negative melanoma.
黑色素瘤的特征是存在驱动和失活功能突变，促进丝裂原活化蛋白激酶（MAPK）信号传导。MEK 抑制剂已被批准用于 BRAF 突变型黑色素瘤；然而，早期临床试验显示在驱动阴性黑色素瘤中偶尔有反应，这表明其他改变赋予了 MAPK/ERK 依赖性。为了鉴定黑色素瘤中的其他结构改变，我们使用新型基于人群的算法在癌症基因组图谱（TCGA）中评估了一组已知的 MAPK/ERK 调节剂的 RNA-Seq。我们在 TCGA 中的黑色素瘤中发现了 1.7%的 MAP3K8 重排，在没有已知驱动突变的肿瘤中发生频率超过 15%（）。使用独立的肿瘤集，我们通过 FISH 验证了类似的重排频率。MAP3K8 重排的黑色素瘤具有低突变负担和不存在典型的 UV 突变模式。我们鉴定了两个具有内源性截断 MAP3K8 重排的黑色素瘤细胞系，这些细胞系表现出极高的依赖性。黑色素瘤细胞中 MAP3K8 基因座的重排和扩增导致截短、活性 MAP3K8 蛋白水平升高；异常 MAP3K8 的致癌依赖性；以及对 BRAF 抑制的协同抗性和对 MEK 或 ERK1/2 抑制的敏感性。我们的发现揭示了驱动突变阴性黑色素瘤中可靶向的致癌 MAP3K8 截断重排，并对这些肿瘤的治疗方法提供了深入了解。这些数据为在携带截断 MAP3K8 重排的驱动阴性、MAPK/ERK 依赖性黑色素瘤中使用 MEK 或 ERK 抑制剂提供了依据。
