title: Resistance to tyrosine kinase inhibitors in clear cell renal cell carcinoma: from the patient's bed to molecular mechanisms.
abstract: 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.
authors.affiliation: Military Institute of Medicine, Warsaw, Poland. Electronic address: mbuczek86@gmail.com.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Buczek
authors.affiliation: Institut Gustave Roussy, Villejuif, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Escudier
authors.affiliation: Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw and Institute of Biochemistry and Biophysics, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Bartnik
authors.affiliation: Military Institute of Medicine, Warsaw, Poland.
authors.forename: Cezary
authors.initials: C
authors.lastname: Szczylik
authors.affiliation: Military Institute of Medicine, Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Czarnecka
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: D047428:Protein Kinase Inhibitors; D042461:Vascular Endothelial Growth Factor A; D011505:Protein-Tyrosine Kinases
keywords: Acquired and intrinsic resistance; Angiogenesis; Clear cell renal cell carcinoma; Drug resistance; Tyrosine kinase inhibitors