Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer.
Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer.
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DOI：
10.1158/2159-8274.cd-11-0005
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发表时间：
2011-06
期刊：
影响因子：
28.2
通讯作者：
Meyerson M
中科院分区：
文献类型：
--
作者：
Hammerman PS;Sos ML;Ramos AH;Xu C;Dutt A;Zhou W;Brace LE;Woods BA;Lin W;Zhang J;Deng X;Lim SM;Heynck S;Peifer M;Simard JR;Lawrence MS;Onofrio RC;Salvesen HB;Seidel D;Zander T;Heuckmann JM;Soltermann A;Moch H;Koker M;Leenders F;Gabler F;Querings S;Ansén S;Brambilla E;Brambilla C;Lorimier P;Brustugun OT;Helland A;Petersen I;Clement JH;Groen H;Timens W;Sietsma H;Stoelben E;Wolf J;Beer DG;Tsao MS;Hanna M;Hatton C;Eck MJ;Janne PA;Johnson BE;Winckler W;Greulich H;Bass AJ;Cho J;Rauh D;Gray NS;Wong KK;Haura EB;Thomas RK;Meyerson M
虽然基因组靶向疗法改善了肺腺癌患者的治疗效果，但对于驱动肺鳞状细胞癌的基因组改变却知之甚少。对酪氨酸激酶组进行的桑格测序在3.8%的肺鳞状细胞癌和细胞系中发现了DDR2激酶基因的突变。含有DDR2突变的肺鳞状细胞癌细胞系可通过RNA干扰敲低DDR2或用多靶点激酶抑制剂达沙替尼治疗而被选择性杀死。由DDR2突变细胞系建立的肿瘤在异种移植模型中对达沙替尼敏感。突变的DDR2表达导致细胞转化，而这种转化可被达沙替尼阻断。一名对达沙替尼和厄洛替尼治疗有反应的肺鳞状细胞癌患者存在DDR2激酶结构域突变。这些数据表明，DDR2的功能获得性突变是重要的致癌事件，并且可通过达沙替尼进行治疗。由于达沙替尼已被批准使用，这些发现可迅速转化为临床试验。
While genomically targeted therapies have improved outcomes for patients with lung adenocarcinoma, little is known about the genomic alterations which drive squamous cell lung cancer. Sanger sequencing of the tyrosine kinome identified mutations in the DDR2 kinase gene in 3.8% of squamous cell lung cancers and cell lines. Squamous lung cancer cell lines harboring DDR2 mutations were selectively killed by knock-down of DDR2 by RNAi or by treatment with the multi-targeted kinase inhibitor dasatinib. Tumors established from a DDR2 mutant cell line were sensitive to dasatinib in xenograft models. Expression of mutated DDR2 led to cellular transformation which was blocked by dasatinib. A squamous cell lung cancer patient with a response to dasatinib and erlotinib treatment harbored a DDR2 kinase domain mutation. These data suggest that gain-of-function mutations in DDR2 are important oncogenic events and are amenable to therapy with dasatinib. As dasatinib is already approved for use, these findings could be rapidly translated into clinical trials.