Division of Clinical Studies, The Institute of Cancer Research, London, United Kingdom.
The CRUK Gene Function Laboratory and the Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
Cancer Res. 2017 Aug 15;77(16):4279-4292. doi: 10.1158/0008-5472.CAN-16-2550. Epub 2017 Jun 20.
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). Functional ALK dependency was confirmed and 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 , synergistic effects were observed upon drug combination. , 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. .
尽管对肉瘤（一种源自结缔组织的恶性肿瘤）进行了强化的多模式治疗，但患者的生存情况仍较差。基于候选药物的靶向治疗仅取得了有限的临床成功，这促使我们对致癌信号网络进行无偏且全面的分析，以揭示治疗靶点和个性化治疗策略。在此，我们采用基于质谱的磷酸化蛋白质组学分析方法，对迄今为止鉴定的最大且最具异质性的肉瘤细胞系进行分析，确定了新的酪氨酸磷酸化模式、特定亚型中增强的酪氨酸激酶以及潜在的驱动激酶。通过表达具有较大细胞外结构域缺失的 ALK 变体，我们在 Aska-SS 滑膜肉瘤（SS）细胞系中鉴定出了新型的驱动基因 ALK。并通过选择性抑制剂进行了功能依赖性的确认。重要的是，在 43 例 SS 患者标本中的 6 例（14%）中检测到了 ALK 免疫阳性，其中 1 例存在 ALK 重排。SS 细胞系还表现出较高的 PDGFRα 磷酸化，这伴随着 Yamato-SS 细胞中 MET 的激活增强。尽管 Yamato-SS 细胞对克唑替尼（ALK/MET 抑制剂）敏感，但对单独使用帕唑帕尼（VEGFR/PDGFR 抑制剂）不敏感，但联合用药时可观察到协同作用。单独使用这两种药物均有效，帕唑帕尼的疗效可能归因于血管生成减少。在 58%和 84%的 SS 患者中分别检测到 MET 或 PDGFRα 的表达，56%的患者存在共表达。因此，我们的综合方法确定了 ALK 和 MET 作为 SS 有前途的治疗靶点。
