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Targeting TSLP-induced tyrosine kinase signaling pathways in CRLF2-rearranged Ph-like ALL
Molecular Cancer Research ( IF 5.2 ) Pub Date : 2020-08-14 , DOI: 10.1158/1541-7786.mcr-19-1098
Keith C S Sia 1 , Ling Zhong 2 , Chelsea Mayoh 1 , Murray D Norris 1, 3 , Michelle Haber 1 , Glenn M Marshall 1, 4 , Mark J Raftery 2 , Richard B Lock 1, 3
Affiliation  

Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) is characterized by aberrant activation of signaling pathways and high risk of relapse. Approximately 50% of Ph-like ALL cases overexpress cytokine receptor-like factor 2 (CRLF2) associated with gene rearrangement. Activated by its ligand thymic stromal lymphopoietin (TSLP), CRLF2 signaling is critical for the development, proliferation, and survival of normal lymphocytes. To examine activation of tyrosine kinases regulated by TSLP/CRLF2, phosphotyrosine (P-Tyr) profiling coupled with stable isotope labeling of amino acids in cell culture (SILAC) was conducted using two CRLF2-rearranged (CRLF2r) Ph-like ALL cell lines stimulated with TSLP. As a result, increased P-Tyr was detected in previously reported TSLP-activated tyrosine kinases and substrates, including JAK1, JAK2, STAT5, and ERK1/2. Interestingly, TSLP also increased P-Tyr of insulin growth factor 1 receptor (IGF1R) and fibroblast growth factor receptor 1 (FGFR1), both of which can be targeted with small-molecule inhibitors. Fixed-ratio combination cytotoxicity assays using the tyrosine kinase inhibitors BMS-754807 and ponatinib that target IGF1R and FGFR1, respectively, revealed strong synergy against both cell line and patient-derived xenograft (PDX) models of CRLF2r Ph-like ALL. Further analyses also indicated off-target effects of ponatinib in the synergy, and novel association of the Ras-associated protein-1 (Rap1) signaling pathway with TSLP signaling in CRLF2r Ph-like ALL. When tested in vivo, the BMS-754807/ponatinib combination exerted minimal efficacy against 2 Ph-like ALL PDXs, associated with low achievable plasma drug concentrations. Although this study identified potential new targets in CRLF2r Ph-like ALL, it also highlights that in vivo validation of synergistic drug interactions is essential. Implication: Quantitative phosphotyrosine profiling identified potential therapeutic targets for high-risk CRLF2-rearranged Ph-like ALL.

中文翻译:

在 CRLF2 重排的 Ph 样 ALL 中靶向 TSLP 诱导的酪氨酸激酶信号通路

费城 (Ph) 样急性淋巴细胞白血病 (ALL) 的特征是信号通路异常激活和高复发风险。大约 50% 的 Ph 样 ALL 病例过度表达与基因重排相关的细胞因子受体样因子 2 (CRLF2)。CRLF2 信号由其配体胸腺基质淋巴细胞生成素 (TSLP) 激活,对正常淋巴细胞的发育、增殖和存活至关重要。为了检查由 TSLP/CRLF2 调节的酪氨酸激酶的激活,使用两种 CRLF2 重排 (CRLF2r) Ph 样 ALL 细胞系刺激进行磷酸酪氨酸 (P-Tyr) 分析与细胞培养中氨基酸的稳定同位素标记 (SILAC)与 TSLP。因此,在先前报道的 TSLP 激活的酪氨酸激酶和底物(包括 JAK1、JAK2、STAT5 和 ERK1/2)中检测到 P-Tyr 增加。有趣的是,TSLP 还增加了胰岛素生长因子 1 受体 (IGF1R) 和成纤维细胞生长因子受体 1 (FGFR1) 的 P-Tyr,两者都可以被小分子抑制剂靶向。使用分别靶向 IGF1R 和 FGFR1 的酪氨酸激酶抑制剂 BMS-754807 和 ponatinib 的固定比率组合细胞毒性测定显示,对 CRLF2r Ph 样 ALL 的细胞系和患者来源的异种移植 (PDX) 模型具有很强的协同作用。进一步的分析还表明帕纳替尼在协同作用中的脱靶效应,以及 Ras 相关蛋白 1 (Rap1) 信号通路与 CRLF2r Ph 样 ALL 中的 TSLP 信号通路的新关联。在体内测试时,BMS-754807/ponatinib 组合对 2 Ph 样 ALL PDX 的疗效最小,与可达到的血浆药物浓度低有关。虽然这项研究确定了 CRLF2r Ph 样 ALL 的潜在新靶点,但它也强调了协同药物相互作用的体内验证是必不可少的。意义:定量磷酸酪氨酸分析确定了高风险 CRLF2 重排 Ph 样 ALL 的潜在治疗靶点。
更新日期:2020-08-14
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