Buczek Magdalena, Escudier Bernard, Bartnik Ewa, Szczylik Cezary, Czarnecka Anna
Military Institute of Medicine, Warsaw, Poland.
Institut Gustave Roussy, Villejuif, France.
Biochim Biophys Acta. 2014 Jan;1845(1):31-41. doi: 10.1016/j.bbcan.2013.10.001. Epub 2013 Oct 14.
The introduction of anti-angiogenic drugs especially tyrosine kinase inhibitors (TKIs) was a breakthrough in the treatment of renal cell carcinoma (RCC). Although TKIs have significantly improved outcome in patients with metastatic disease, the majority still develop resistance over time. Because different combinations and sequences of TKIs are tested in clinical trials, resistance patterns and mechanisms underlying this phenomenon should be thoroughly investigated. From a clinical point of view, resistance occurs either as a primary phenomenon (intrinsic) or as a secondary phenomenon related to various escape/evasive mechanisms that the tumor develops in response to vascular endothelial growth factor (VEGF) inhibition. Intrinsic resistance is less common, and related to the primary redundancy of available angiogenic signals from the tumor, causing unresponsiveness to VEGF-targeted therapies. Acquired resistance in tumors is associated with activation of an angiogenic switch which leads to either upregulation of the existing VEGF pathway or recruitment of alternative factors responsible for tumor revascularization. Multiple mechanisms can be involved in different tumor settings that contribute both to evasive and intrinsic resistance, and current endeavor aims to identify these processes and assess their importance in clinical settings and design of pharmacological strategies that lead to enduring anti-angiogenic therapies.
抗血管生成药物尤其是酪氨酸激酶抑制剂（TKIs）的引入是肾细胞癌（RCC）治疗的一项突破。尽管TKIs显著改善了转移性疾病患者的预后，但大多数患者最终仍会产生耐药性。由于在临床试验中测试了不同的TKIs组合和用药顺序，因此应深入研究这种现象背后的耐药模式和机制。从临床角度来看，耐药性既可以是一种原发性现象（固有耐药），也可以是与肿瘤针对血管内皮生长因子（VEGF）抑制所产生的各种逃逸机制相关的继发性现象。固有耐药不太常见，与肿瘤中可用血管生成信号的原发性冗余有关，导致对VEGF靶向治疗无反应。肿瘤中的获得性耐药与血管生成开关的激活有关，这会导致现有VEGF途径上调或募集负责肿瘤再血管化的替代因子。多种机制可能参与不同的肿瘤情况，导致逃逸性耐药和固有耐药，目前的努力旨在识别这些过程，并评估它们在临床环境中的重要性以及设计能带来持久抗血管生成治疗的药理学策略。
