Resistance to tyrosine kinase inhibitors in clear cell renal cell carcinoma: From the patient’s bed to molecular mechanisms
Cet article passe en revue les travaux récents sur les mécanismes de résistance aux inhibiteurs de tyrosine kinase dans les traitements de patients atteints d'un carcinome rénal à cellules claires
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, assess their importance in clinical settings and design of pharmacological strategies that lead to enduring anti-angiogenic therapies.
http://www.sciencedirect.com/science/article/pii/S0304419X13000437