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.

Metabolic tumor burden is associated with major oncogenomic alterations and serum tumor markers in patients with resected pancreatic cancer

“…It is well established that TP53, CDKN2A/p16, and SMAD4/DPC4 mutations occur during pancreatic carcinogenesis, but it is unknown whether these mutations are associated with the abnormal metabolic tumor burden detected by 18 F-FDG PET/CT. Nevertheless, abnormal expression profiles of TP53, CDKN2A/p16, and SMAD4/DPC4 are known to contribute to tumor malignancies and treatment-resistance [23][24][25][26][27]. Activation of transcription factor TP53 in response to a series of stimuli and stresses induces signaling pathways that affect anticancer mechanisms, including DNA repair, cell-cycle arrest and apoptosis.…”

Potential molecular, cellular and microenvironmental mechanism of sorafenib resistance in hepatocellular carcinoma

“…Recently, the correlation between EMT and the adoption of cancer stemness has been extensively studied as a hot research topic. From the cellular point of view, the involvement of EMT can also be used to clarify the mechanism under the acquired resistance to sorafenib [99]. Via EMT, the epithelial cells overexpressed mesenchymal biomarkers and CSC markers and silenced CSC gain migratory ability [100].…”

Recent Aspects of Sunitinib Therapy in Patients with Metastatic Clear-Cell Renal Cell Carcinoma: a Systematic Review of the Literature

“…The development of targeted agent resistance occurs when the tumor becomes independent on the constitutive activity of signaling pathways; this event can be caused to some genetic variations which typically determine the impossibility of appropriate drug binding as a consequence of impaired or lack of crucial proteins [63].…”

“…In particular, 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 VEGF inhibition [63,64].…”

“…However, acquired resistance in ccRCC may result a reversible event [63]: as demonstrated in several studies, the protracted exposure of tumor cells to sunitinib constantly results in drug resistance development in vitro [65,66]. Gotink et al in 2011 verified that sensitivity to sunitinib may be progressively restored after a 12-week period of drug-free culture [67].…”