Gene expression profile identifies tyrosine kinase c-Met as a targetable mediator of antiangiogenic therapy resistance.
Gene expression profile identifies tyrosine kinase c-Met as a targetable mediator of antiangiogenic therapy resistance.
复制标题
DOI：
10.1158/1078-0432.ccr-12-1281
复制
发表时间：
2013-04-01
期刊：
影响因子：
--
通讯作者：
Aghi MK
中科院分区：
文献类型：
--
作者：
Jahangiri A;De Lay M;Miller LM;Carbonell WS;Hu YL;Lu K;Tom MW;Paquette J;Tokuyasu TA;Tsao S;Marshall R;Perry A;Bjorgan KM;Chaumeil MM;Ronen SM;Bergers G;Aghi MK
鉴定胶质母细胞瘤抗血管生成治疗耐药的介质，并在异种移植物中靶向这些介质。我们进行了微阵列分析比较贝伐珠单抗耐药的胶质母细胞瘤（BRG），治疗前的肿瘤从相同的患者。我们建立了抗血管生成疗法对靶向候选抗性介质的抗性的新型异种移植物模型。BRG微阵列分析显示受体酪氨酸激酶c-Met相对于预处理的上调，由于其先前作为贝伐单抗抗性介体的生物相容性而进行了进一步的研究。与预处理相比，BRG表现出缺氧增加，其方式与其c-Met上调、c-Met磷酸化增加以及c-Met激活的粘着斑激酶（FAK）和STAT 3磷酸化增加相关。我们开发了两种新的抗血管生成治疗耐药异种移植模型。在第一个模型中，对最初有反应的异种移植物进行连续贝伐珠单抗治疗产生了具有获得性贝伐珠单抗耐药性的异种移植物，其表现出与治疗前相比c-Met表达上调。在第二个模型中，BRG来源的异种移植物对MRI肿瘤血管系统改变和贝伐单抗的生存促进作用保持不应性。该BRG衍生的异种移植物的生长被c-Met抑制剂抑制。用c-Met shRNA转导这些异种移植细胞抑制了它们在缺氧中的侵袭和存活，破坏了它们的间充质形态，并将它们从贝伐珠单抗抗性转化为贝伐珠单抗应答性。工程化贝伐珠单抗应答细胞以表达组成型活性c-Met，导致这些细胞形成贝伐珠单抗耐药异种移植物。这些发现支持c-Met在缺氧和侵袭中的存活中的作用，与抗血管生成疗法抗性相关的特征;以及对抗血管生成疗法抗性的异种移植物的生长和治疗抗性。治疗靶向c-Met可以预防或克服抗血管生成治疗耐药性。
To identify mediators of glioblastoma anti-angiogenic therapy resistance and target these mediators in xenografts. We performed microarray analysis comparing bevacizumab-resistant glioblastomas (BRGs) to pre-treatment tumors from the same patients. We established novel xenograft models of anti-angiogenic therapy resistance to target candidate resistance mediator(s). BRG microarray analysis revealed upregulation versus pre-treatment of receptor tyrosine kinase c-Met, which underwent further investigation because of its prior biologic plausibility as a bevacizumab resistance mediator. BRGs exhibited increased hypoxia versus pre-treatment in a manner correlating with their c-Met upregulation, increased c-Met phosphorylation, and increased phosphorylation of c-Met-activated focal adhesion kinase (FAK) and STAT3. We developed two novel xenograft models of anti-angiogenic therapy resistance. In the first model, serial bevacizumab treatment of an initially responsive xenograft generated a xenograft with acquired bevacizumab resistance, which exhibited upregulated c-Met expression versus pre-treatment. In the second model, a BRG-derived xenograft maintained refractoriness to the MRI tumor vasculature alterations and survival-promoting effects of bevacizumab. Growth of this BRG-derived xenograft was inhibited by a c-Met inhibitor. Transducing these xenograft cells with c-Met shRNA inhibited their invasion and survival in hypoxia, disrupted their mesenchymal morphology, and converted them from bevacizumab-resistant to bevacizumab-responsive. Engineering bevacizumab-responsive cells to express constitutively active c-Met caused these cells to form bevacizumab-resistant xenografts. These findings support the role of c-Met in survival in hypoxia and invasion, features associated with anti-angiogenic therapy resistance; and growth and therapeutic resistance of xenografts resistant to anti-angiogenic therapy. Therapeutically targeting c-Met could prevent or overcome anti-angiogenic therapy resistance.