Validation of PDGFRβ and c-Src tyrosine kinases as tumor/vessel targets in patients with multiple myeloma:: preclinical efficacy of the novel, orally available inhibitor dasatinib
Validation of PDGFRβ and c-Src tyrosine kinases as tumor/vessel targets in patients with multiple myeloma:: preclinical efficacy of the novel, orally available inhibitor dasatinib
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DOI：
10.1182/blood-2007-10-116590
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发表时间：
2008-08-15
期刊：
影响因子：
20.3
通讯作者：
Vacca, Angelo
中科院分区：
文献类型：
--
作者：
Coluccia, Addolorata Maria Luce;Cirulli, Teresa;Vacca, Angelo
在允许的骨髓微环境中抑制多发性骨髓瘤(MM)浆细胞是阻止与疾病进展相关的肿瘤/血管生长的一个有吸引力的策略。然而，靶标特异性是这种方法的一个基本目标。在此，我们鉴定了血小板衍生生长因子(PDGF)受体β(PDGFRβ)和pp60c-Src是MM患者分离的浆细胞和内皮细胞(MMECs)中共有的结构性激活的酪氨酸激酶(TKs)。我们的细胞和分子解剖显示，PDGF-BB/PDGFRβ激动轴通过激活ERK1/2、AKT，以及MMEC释放的促血管生成因子，如血管内皮生长因子(VEGF)和白介素8(IL-8)的转录，促进MM肿瘤的生长和血管的萌生。有趣的是，在MM肿瘤和内皮细胞中，pp60c-Src TK活性是由VEGF选择性地诱导的，并且使用小干扰(Si)RNA证实了pp60c-Src是MMEC存活、迁移和血管生成所需的VEGF环的关键信号效应因子。我们还评估了达沙替尼的抗肿瘤/血管活性，达沙替尼是一种新型口服生物活性PDGFRβ/Src TK抑制剂，可显著延缓MM肿瘤的生长和体内血管生成，显示出与传统和新型抗骨髓瘤药物(即马法兰、泼尼松、硼替佐米和沙利度胺)的协同细胞毒性。总体数据强调了联合靶向PDGFRβ/c-Src TKs在多发性骨髓瘤中的生物学和治疗相关性，为未来的临床试验提供了框架。
Inhibition of multiple myeloma (MM) plasma cells in their permissive bone marrow microenvironment represents an attractive strategy for blocking the tumor/vessel growth associated with the disease progression. However, target specificity is an essential aim of this approach. Here, we identified platelet-derived growth factor (PDGF)-receptor beta (PDGFR beta) and pp60c-Src as shared constitutively activated tyrosine-kinases (TKs) in plasma cells and endothelial cells (ECs) isolated from MM patients (MMECs). Our cellular and molecular dissection showed that the PDGF-BB/PDGFR beta kinase axis promoted MM tumor growth and vessel sprouting by activating ERK1/2, AKT, and the transcription of MMEC-released proangiogenic factors, such as vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8). Interestingly, pp60c-Src TK-activity was selectively induced by VEGF in MM tumor and ECs, and the use of smallinterfering (si)RNAs validated pp60c-Src as a key signaling effector of VEGF loop required for MMEC survival, migration, and angiogenesis. We also assessed the antitumor/vessel activity of dasatinib, a novel orally bioactive PDGFR beta/Src TK-inhibitor that significantly delayed MM tumor growth and angiogenesis in vivo, showing a synergistic cytotoxicity with conventional and novel antimyeloma drugs (ie, melphalan, prednisone, bortezomib, and thalidomide). Overall data highlight the biologic and therapeutic relevance of the combined targeting of PDGFR beta/c-Src TKs in MM, providing a framework for future clinical trials.