Kinase activity profiling in renal cell carcinoma, benign renal tissue and in response to four different tyrosine kinase inhibitors
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Andliena Tahiri1,2,3, Katarina Puco4, Faris Naji5, Vessela N. Kristensen1,2, Glenny Cecilie Alfsen1,6, Lorant Farkas1,6, Frode S. Nilsen1,7, Stig Müller1,7,*, Jan Oldenburg1,4,* and Jürgen Geisler1,4,*
1 Institute of Clinical Medicine, University of Oslo, Oslo, Norway
2 Department of Medical Genetics, Oslo University Hospital, Ullevål, Norway
3 Department of Clinical Molecular Biology (EpiGen), Akershus University Hospital, Lørenskog, Norway
4 Department of Oncology, Akershus University Hospital, Lørenskog, Norway
5 Pamgene International BV, ‘s-Hertogenbosch, The Netherlands
6 Department of Pathology, Akershus University Hospital, Lørenskog, Norway
7 Department of Urology, Akershus University Hospital, Lørenskog, Norway
* These authors contributed equally to this work
Keywords: kidney cancer; kinase activity; tyrosine kinase inhibitors; renal cell carcinoma; tyrosine kinase
Received: June 06, 2022 Accepted: July 01, 2022 Published: August 04, 2022
Kinase activity is frequently altered in renal cell carcinoma (RCC), and tyrosine kinase inhibitors (TKIs) are part of the standard treatment strategy in patients with metastatic disease. However, there are still no established biomarkers to predict clinical benefits of a specific TKI. Here, we performed protein tyrosine kinase (PTK) profiling using PamChip® technology. The aim of this study was to identify differences in PTK activity between normal and malignant kidney tissue obtained from the same patient, and to investigate the inhibitory effects of TKIs frequently used in the clinics: sunitinib, pazopanib, cabozantinib and tivozanib. Briefly, our results showed that 36 kinase substrates differs (FDR < 0.05) between normal and cancer kidney tissue, where members of the Src family kinases and the phosphoinositide-3-kinase (PI3K) pathway exhibit high activity in renal cancer. Furthermore, ex vivo treatment of clear cell RCC with TKIs revealed that pathways such as Rap1, Ras and PI3K pathways were strongly inhibited, whereas the neurotrophin pathway had increased activity upon TKI addition. In our assay, tivozanib and cabozantinib exhibited greater inhibitory effects on PTK activity compared to sunitinib and pazopanib, implying they might be better suitable as TKIs for selected RCC patients.
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