title: Mechanisms of Acquired Resistance to Tyrosine Kinase Inhibitors in Clear - Cell Renal Cell Carcinoma (ccRCC).
abstract: Clear - cell renal cell carcinoma (ccRCC) is a histological subtype of renal cell carcinoma - the most prevalent adult kidney cancer. Causes of ccRCC are not completely understood and therefore number of available therapies is limited. As a consequence of tumor chemo- and radioresistance as well as restrictions in offered targeted therapies, overall response rate is still unsatisfactory. Moreover, a significant group of patients (circa 1/4) does not respond to the targeted first-line treatment, while in other cases, after an initial period of stable improvement, disease progression occurs. Owing to this, more data on resistance mechanisms are needed, especially those concerning widely used, relatively lately approved and more successful than previous therapies - tyrosine kinase inhibitors (TKIs). Up to date, five TKIs have been licensed for ccRCC treatment: sunitinib (SUTENT®, Pfizer Inc.), sorafenib (Nexavar®, Bayer HealthCare/Onyx Pharmaceuticals), pazopanib (Votrient®, GlaxoSmithKline), axitinib (Inlyta®, Pfitzer Inc.) and tivozanib (AV-951®, AVEO Pharmaceuticals). Researchers have specified different subsets of tyrosine kinase inhibitors potential resistance mechanisms in clear-cell renal cell carcinoma. In most papers published until now, drug resistance is divided into intrinsic and acquired, and typically multi-drug resistance (MDR) protein is described. Herein, the authors focus on molecular analysis concerning acquired, non-genetic resistance to TKIs, with insight into specific biological processes.
authors.affiliation: Department of Oncology with Laboratory of Molecular Oncology, Military Institute of Medicine in Warsaw, Poland ; Postgraduate School of Molecular Medicine, Medical University of Warsaw, Poland.
authors.forename: Zofia F
authors.initials: ZF
authors.lastname: Bielecka
authors.affiliation: Department of Oncology with Laboratory of Molecular Oncology, Military Institute of Medicine in Warsaw, Poland.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Czarnecka
authors.affiliation: Department of Oncology with Laboratory of Molecular Oncology, Military Institute of Medicine in Warsaw, Poland ; Postgraduate School of Molecular Medicine, Medical University of Warsaw, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Solarek
authors.affiliation: Department of Oncology with Laboratory of Molecular Oncology, Military Institute of Medicine in Warsaw, Poland ; I Faculty of Medicine, Medical University of Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Kornakiewicz
authors.affiliation: Department of Oncology with Laboratory of Molecular Oncology, Military Institute of Medicine in Warsaw, Poland.
authors.forename: Cezary
authors.initials: C
authors.lastname: Szczylik
keywords: Acquired drug resistance; angiogenic switch; anti-angiogenic therapy; axitinib; clear-cell renal cell carcinoma; epithelial-mesenchymal transition; non-genetic resistance mechanisms.; pazopanib; sorafenib; sunitinib; tivozanib; tyrosine kinase inhibitors