PP6C hotspot mutations in melanoma display sensitivity to Aurora kinase inhibition.
PP6C hotspot mutations in melanoma display sensitivity to Aurora kinase inhibition.
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DOI：
10.1158/1541-7786.mcr-13-0422
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发表时间：
2014-03
期刊：
影响因子：
--
通讯作者：
Gardner LB
中科院分区：
文献类型：
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作者：
Gold HL;Wengrod J;de Miera EV;Wang D;Fleming N;Sikkema L;Kirchhoff T;Hochman T;Goldberg JD;Osman I;Gardner LB
最近的全基因组黑色素瘤测序研究已经确定了编码丝氨酸/苏氨酸磷酸酶6（PPP 6C/PP 6C）催化亚基的基因中的复发性突变。然而，这些突变的生化，功能和临床后果是未知的。对黑色素瘤患者（233例原发性和77例转移性标本）的PP 6C进行测序，扩展了前瞻性临床结果，揭示了原发性和转移性黑色素瘤患者中的大量热点突变。尽管原发性患者中PP 6C突变的分期和存在之间的关联很小，但每个肿瘤中的细胞亚群确实含有PP 6C突变，这表明PP 6C突变是黑色素瘤中的早期但非肿瘤起始事件。在原发性PP 6C突变患者中，与无终止突变患者相比，终止突变患者的无复发生存期显著缩短。此外，PP 6C突变与常见的BRAF和NRAS突变无关。在生物化学上，PP 6C突变可以分为与PP 6C调节亚基相互作用的突变和不与PP 6C调节亚基相互作用的突变。不与PP 6C调节亚基结合的突变与极光激酶（PP 6C底物）磷酸化增加和有丝分裂缺陷相关。然而，两类PP 6C突变导致对Aurora激酶抑制的敏感性增加。总之，这些数据首次支持PP 6C突变在分子、生化和临床上是异质性的。PP 6C突变在黑色素瘤中具有独特的功能和临床后果，并赋予对Aurora A激酶抑制剂的敏感性
Recent whole genome melanoma sequencing studies have identified recurrent mutations in the gene encoding the catalytic subunit of serine/threonine phosphatase 6 (PPP6C/PP6C). However the biochemical, functional, and clinical ramifications of these mutations are unknown. Sequencing PP6C from melanoma patients (233 primary and 77 metastatic specimens) with extended prospective clinical outcome revealed a large number of hotspot mutations in both primary and metastatic melanoma patients. Despite minimal association between stage and presence of PP6C mutations in primary patients, a subpopulation of cells within each tumor did contain PP6C mutations, suggesting PP6C mutation is an early, but non tumor-initiating event in melanoma. Among primary patients with PP6C mutations, patients with stop mutations had significantly shorter recurrence-free survival compared to patients without stop mutations. In addition, PP6C mutations were independent of commonly observed BRAF and NRAS mutations. Biochemically, PP6C mutations could be classified as those that interact with PP6C regulatory subunits and those that do not. Mutations that did not bind to PP6C regulatory subunits were associated with increased phosphorylation of Aurora kinase, a PP6C substrate, and mitotic defects. However, both classes of PP6C mutations led to increased sensitivity to Aurora kinase inhibition. Together, these data support for the first time that PP6C mutations are molecularly, biochemically, and clinically heterogenous. PP6C mutations have distinct functional and clinical consequences in melanoma, and confer sensitivity to Aurora A kinase inhibitors