Abstract
Despite the widespread use of kinase-targeted agents in clear cell renal cell carcinoma (CC-RCC), comprehensive kinase activity evaluation (kinomic profiling) of these tumors is lacking. Thus, kinomic profiling of CC-RCC may assist in devising a classification system associated with clinical outcomes, and help identify potential therapeutic targets. Fresh frozen CC-RCC tumor lysates from 41 clinically annotated patients who had localized disease at diagnosis were kinomically profiled using the PamStation®12 high-content phospho-peptide substrate microarray system (PamGene International). Twelve of these patients also had matched normal kidneys available that were also profiled. Unsupervised hierarchical clustering and supervised comparisons based on tumor vs. normal kidney and clinical outcome (tumor recurrence) were performed and coupled with advanced network modeling and upstream kinase prediction methods. Unsupervised clustering analysis of localized CC-RCC tumors identified 3 major kinomic groups associated with inflammation (A), translation initiation (B), and immune response and cell adhesions (C) processes. Potential driver kinases implicated include PFTAIRE (PFTK1), PKG1, and SRC, which were identified in groups A, B, and C, respectively. Of the 9 patients who had tumor recurrence, only one was found in Group B. Supervised analysis showed decreased kinase activity of CDK1 and RSK1-4 substrates in those which progressed compared to others. Twelve tumors with matching normal renal tissue implicated increased PIM’s and MAPKAPK’s in tumors compared to adjacent normal renal tissue. As such, comprehensive kinase profiling of CC-RCC tumors could provide a functional classification strategy for patients with localized disease and identify potential therapeutic targets.
Highlights
Clear cell (CC)-renal cell carcinoma (RCC) is a chemotherapy and radiation resistant tumor affecting approximately 50,000 patients per year in the United States.[1]
Several kinase-directed therapies targeting vascular endothelial growth factor (VEGF) and mammalian target of rapamycin have been approved for clear cell renal cell carcinoma (CC-RCC) while several novel kinase-targeted agents are in various stages of preclinical and clinical development for this disease
Antibodies and small molecule inhibitors targeting kinase dependent pathways are in clinical use for advanced disease including sorafenib, sunitinib, axitinib (VEGFR1-3, PDGFR, c-KIT), bevacizumab, pazopanib (VEGFR1-3, PDFGR, c-KIT), everolimus and temsirolimus.[7, 8]
Summary
Clear cell (CC)-renal cell carcinoma (RCC) is a chemotherapy and radiation resistant tumor affecting approximately 50,000 patients per year in the United States.[1]. Antibodies and small molecule inhibitors targeting kinase dependent pathways are in clinical use for advanced disease including sorafenib (targeting VEGFR, PDGFR, Raf), sunitinib (targeting VEGFR, PDGFR, cKIT, CSF1R, FLT3, RET), axitinib (VEGFR1-3, PDGFR, c-KIT), bevacizumab (binding VEGF-A), pazopanib (VEGFR1-3, PDFGR, c-KIT), everolimus and temsirolimus (targeting mTOR).[7, 8] Agents targeting c-Met and FGFR in addition to VEGFRs (cabozantinib and lenvatinib) appear promising and are being developed.[9,10,11].cabozantinib was recently reported to significantly extend progression-free survival following prior VEGF inhibitors in a phase III trial and is likely to be approved for commercial use [12]
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