Mechanisms of Acquired Resistance to Tyrosine Kinase Inhibitors in Clear - Cell Renal Cell Carcinoma (ccRCC)
Zofia F. Bielecka, Anna M. Czarnecka, Wojciech Solarek, Anna Kornakiewicz and Cezary Szczylik
Affiliation: Laboratory of Molecular Oncology, Department of Oncology, Military Institute of Medicine in Warsaw, Szaserów 128, 04-141 Warsaw, Poland.
Keywords: Acquired drug resistance, tyrosine kinase inhibitors, sunitinib, sorafenib, pazopanib, axitinib, tivozanib, epithelialmesenchymal
transition, angiogenic switch, anti-angiogenic therapy, clear-cell renal cell carcinoma, non-genetic resistance
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.
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