Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.
Mol Cancer Res. 2011 Jun;9(6):801-12. doi: 10.1158/1541-7786.MCR-10-0512. Epub 2011 Apr 26.
Therapies directed against receptor tyrosine kinases are effective in many cancer subtypes, including lung and breast cancer. We used a phosphoproteomic platform to identify active receptor tyrosine kinases that might represent therapeutic targets in a panel of 25 melanoma cell strains. We detected activated receptors including TYRO3, AXL, MERTK, EPHB2, MET, IGF1R, EGFR, KIT, HER3, and HER4. Statistical analysis of receptor tyrosine kinase activation as well as ligand and receptor expression indicates that some receptors, such as FGFR3, may be activated via autocrine circuits. Short hairpin RNA knockdown targeting three of the active kinases identified in the screen, AXL, HER3, and IGF1R, inhibited the proliferation of melanoma cells and knockdown of active AXL also reduced melanoma cell migration. The changes in cellular phenotype observed on AXL knockdown seem to be modulated via the STAT3 signaling pathway, whereas the IGF1R-dependent alterations seem to be regulated by the AKT signaling pathway. Ultimately, this study identifies several novel targets for therapeutic intervention in melanoma.
针对受体酪氨酸激酶的治疗方法在许多癌症亚型中都有效，包括肺癌和乳腺癌。我们使用磷酸化蛋白质组学平台来鉴定 25 种黑素瘤细胞系中的活跃受体酪氨酸激酶，这些激酶可能成为治疗靶点。我们检测到激活的受体包括 TYRO3、AXL、MERTK、EPHB2、MET、IGF1R、EGFR、KIT、HER3 和 HER4。受体酪氨酸激酶激活以及配体和受体表达的统计分析表明，某些受体（如 FGFR3）可能通过自分泌回路激活。针对筛选中鉴定出的三种活跃激酶（AXL、HER3 和 IGF1R）的短发夹 RNA 敲低抑制了黑素瘤细胞的增殖，而活跃 AXL 的敲低也降低了黑素瘤细胞的迁移。AXL 敲低观察到的细胞表型变化似乎通过 STAT3 信号通路进行调节，而 IGF1R 依赖性改变似乎受 AKT 信号通路调节。最终，这项研究确定了几种新的黑素瘤治疗干预靶点。
