滑膜肉瘤新靶点:ALK和MET基因变异
  • 采用质谱基础上的磷酸化蛋白质组学分析肉瘤细胞株,ALK是Aska-SS细胞株的驱动因子,14%SS患者标本中检出ALK免疫阳性,1例ALK重排;
  • SS细胞株的特征包括PDGFRα高度磷酸化,Yamato-SS细胞中伴随MET活化增强;
  • 尽管在体外Yamato-SS细胞对克唑替尼敏感、对帕唑替尼耐药,联合用药有协同作用,两药体内分别有效;
  • 分别有58%和84%SS患者检出MET或 PDGFRα表达,共表达者为56%,ALK和 MET可能是SS的潜在治疗靶点。
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Cancer Research [IF:9.727]

Phosphoproteomic Profiling Reveals ALK and MET as Novel Actionable Targets across Synovial Sarcoma Subtypes

磷酸化蛋白质组分析揭示ALK和MET是滑膜肉瘤(SS)亚型的新的有效靶点

10.1158/0008-5472.CAN-16-2550

2017-08-15, Article

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Despite intensive multimodal treatment of sarcomas, a heterogeneous group of malignant tumors arising from connective tissue, survival remains poor. Candidate-based targeted treatments have demonstrated limited clinical success, urging an unbiased and comprehensive analysis of oncogenic signaling networks to reveal therapeutic targets and personalized treatment strategies. Here we applied mass spectrometry-based phosphoproteomic profiling to the largest and most heterogeneous set of sarcoma cell lines characterized to date and identified novel tyrosine phosphorylation patterns, enhanced tyrosine kinases in specific subtypes, and potential driver kinases. ALK was identified as a novel driver in the Aska-SS synovial sarcoma (SS) cell line via expression of an ALK variant with a large extracellular domain deletion (ALK(Δ2-17)). Functional ALK dependency was confirmed in vitro and in vivo with selective inhibitors. Importantly, ALK immunopositivity was detected in 6 of 43 (14%) of SS patient specimens, one of which exhibited an ALK rearrangement. High PDGFRα phosphorylation also characterized SS cell lines, which was accompanied by enhanced MET activation in Yamato-SS cells. Although Yamato-SS cells were sensitive to crizotinib (ALK/MET-inhibitor) but not pazopanib (VEGFR/PDGFR-inhibitor) monotherapy in vitro, synergistic effects were observed upon drug combination. In vivo, both drugs were individually effective, with pazopanib efficacy likely attributable to reduced angiogenesis. MET or PDGFRα expression was detected in 58% and 84% of SS patients, respectively, with coexpression in 56%. Consequently, our integrated approach has led to the identification of ALK and MET as promising therapeutic targets in SS. Cancer Res; 77(16); 4279-92. ©2017 AACR.

First Authors:
Emmy D G Fleuren

Correspondence Authors:
Roger J Daly

All Authors:
Emmy D G Fleuren,Myrella Vlenterie,Winette T A van der Graaf,Melissa H S Hillebrandt-Roeffen,James Blackburn,Xiuquan Ma,Howard Chan,Mandy C Magias,Anke van Erp,Laurens van Houdt,Sabri A S Cebeci,Amy van de Ven,Uta E Flucke,Erin E Heyer,David M Thomas,Christopher J Lord,Kieren D Marini,Vijesh Vaghjiani,Tim R Mercer,Jason E Cain,Jianmin Wu,Yvonne M H Versleijen-Jonkers,Roger J Daly

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