Mechanisms of Acquired Resistance to Tyrosine Kinase Inhibitors in Clear - Cell Renal Cell Carcinoma (ccRCC)

Author(s): Zofia F. Bielecka, Anna M. Czarnecka, Wojciech Solarek, Anna Kornakiewicz, Cezary Szczylik

Journal Name: Current Signal Transduction Therapy

Volume 8 , Issue 3 , 2013

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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.

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 mechanisms.

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Article Details

Year: 2013
Published on: 18 April, 2014
Page: [219 - 228]
Pages: 10
DOI: 10.2174/1574362409666140206223014

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