Large-scale Analysis of PDGFRA Mutations in Melanomas and Evaluation of Their Sensitivity to Tyrosine Kinase Inhibitors Imatinib and Crenolanib

被引:43
作者
Dai, Jie [1 ]
Kong, Yan [1 ]
Si, Lu [1 ]
Chi, Zhihong [1 ]
Cui, Chuanliang [1 ]
Sheng, Xinan [1 ]
Mao, Lili [1 ]
Li, Siming [1 ]
Lian, Bin [1 ]
Yang, Ruifeng [2 ]
Liu, Shujing [2 ]
Xu, Xiaowei [2 ]
Guo, Jun [1 ]
机构
[1] Peking Univ, Canc Hosp & Inst, Dept Renal Canc & Melanoma, Key Lab Carcinogenesis & Translat Res,Minist Educ, Beijing 100142, Peoples R China
[2] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA
基金
国家教育部博士点专项基金资助; 中国国家自然科学基金;
关键词
GASTROINTESTINAL STROMAL TUMORS; KIT GENE-MUTATIONS; C-KIT; METASTATIC MELANOMA; OPEN-LABEL; BRAF; RECEPTOR; GROWTH; EXPRESSION; FREQUENCY;
D O I
10.1158/1078-0432.CCR-13-1266
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: Platelet-derived growth factor receptor a (PDGFRA) is a target for tyrosine kinase inhibitor (TKI)-based targeted therapy. Dysregulation of PDGFRA has been reported in many cancers. However, PDGFRA mutations in melanomas have not been well studied. We analyzed the genetic mutations of PDGFRA in Chinese patients with melanoma and determined the inhibitory potency of TKIs, such as imatinib and crenolanib, on mutant PDGFRA. Experimental Design: Of note, 351 melanoma tissue samples were examined for genetic mutations in exons 12, 14, and 18 of PDGFRA. Activities of mutations in response to imatinib and crenolanib were analyzed by Western blotting of tyrosine-phosphorylated PDGFRA and cell proliferation assays. Results: PDGFRA mutations were observed in 4.6% (16 of 351) of melanomas, and these mutations were mainly detected in acral and mucosal melanomas. PDGFRA mutations seem to be mutually exclusive with KIT mutations, but may coexist with BRAF and NRAS mutations. The genetic mutations of PDGFRA were unrelated to the age, thickness, and ulceration status of primary melanomas. Thirteen mutations were not reported before, and five (P577S, V658A, R841K, H845Y, and G853D) of them resulted in strong autophosphorylation of PDGFRA. Crenolanib showed higher potency than imatinib in inhibiting the kinase activity of PDGFRA. Except that V658A mutation was imatinib-resistant, all the other mutations were sensitive to both imatinib and crenolanib. Conclusions: PDGFRA mutations are detected in a small population of melanoma patients. Our study suggests that patients with melanoma harboring certain PDGFRA mutations may benefit from imatinib and crenolanib treatment. (C)2013 AACR.
引用
收藏
页码:6935 / 6942
页数:8
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