Drug resistance in papillary RCC: from putative mechanisms to clinical practicalities.

Papillary renal cell carcinoma (pRCC) is the second most common renal cell carcinoma (RCC) subtype and accounts for 10-15% of all RCCs. Despite clinical need, few pharmacogenomics studies in pRCC have been performed. Moreover, current research fails to adequately include pRCC laboratory models, such as the ACHN or Caki-2 pRCC cell lines. The molecular mechanisms involved in pRCC development and drug resistance are more diverse than in clear-cell RCC, in which inactivation of VHL occurs in the majority of tumours. Drug resistance to multiple therapies in pRCC occurs via genetic alteration (such as mutations resulting in abnormal receptor tyrosine kinase activation or RALBP1 inhibition), dysregulation of signalling pathways (such as GSK3β-EIF4EBP1, PI3K-AKT and the MAPK or interleukin signalling pathways), deregulation of cellular processes (such as resistance to apoptosis or epithelial-to-mesenchymal transition) and interactions between the cell and its environment (for example, through activation of matrix metalloproteinases). Improved understanding of resistance mechanisms will facilitate drug discovery and provide new effective therapies. Further studies on novel resistance biomarkers are needed to improve patient prognosis and stratification as well as drug development.

Nature reviews. Urology. 2019 Oct 10 [Epub]

Anna Brodziak, Paweł Sobczuk, Ewa Bartnik, Michał Fiedorowicz, Camillo Porta, Cezary Szczylik, Anna M Czarnecka

Department of Oncology, Military Institute of Medicine, Warsaw, Poland., Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Warsaw, Poland., Department of Experimental Pharmacology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland., Division of Translational Oncology, IRCCS Istituti Clinici Scientifici Maugeri, Pavia, Italy., Department of Oncology, Military Institute of Medicine, Warsaw, Poland. .