89 (Phospho)proteomics biomarkers for sunitinib response in RCC BACKGROUND The treatment landscape in metastatic renal cell carcinoma (mRCC) has changed dramatically in the past 15 years. Anti-angiogenic tyrosine kinase inhibitors (TKIs), such as sunitinib, sorafenib, axitinib, pazopanib and cabozantinib, are an effective treatment option for patients with mRCC. Since their introduction, the median overall survival (OS) has improved from 15-17 months before 20041-4 to 23-29 months with TKI monotherapy5-7. Combining TKI’s with immune checkpoint inhibitors (ICI) has further improved the 12-month overall survival rate from 72%8 to 90%9,10. With the vast expansion of therapeutic options, optimization of treatment selection strategies for individual patients becomes more important. Sunitinib is an oral multi-targeted TKI targeting mainly the Vascular Endothelial Growth Factor Receptors (VEGFR 1 and 2), Platelet-Derived Growth Factor Receptors (PDGFR-alpha and PDGFR-beta) and stem cell factor receptor (KIT), though many off-target effects are observed11. Patients receiving first-line treatment with sunitinib have a median progression free survival (PFS) of 8.4 - 11 months, with an objective response rate of 25 - 47%7,12. However, all patients eventually relapse due to acquired resistance, and 13-29% does not benefit from treatment at all12-14. Moreover, up to 53% of patients require dose interruptions and in 12% therapy is discontinued because of adverse events12. Sunitinib remains one of the preferred first-line treatment options for patients with favorable-risk clear cell RCC (ccRCC) and non-ccRCC15-17. To improve treatment benefit from sunitinib, a predictive biomarker would be of significant clinical value. Tissue-based baseline predictive biomarkers for sunitinib in RCC are lacking. Although a large number of candidate molecular biomarkers have been under investigation, none have been prospectively validated18. Thus far, most attempts have applied immunohistochemistry, panel DNA or RNA sequencing and PCR for target detection19. However, due to multiple resistance mechanisms in RCC, characteristically driven by a multitude of aberrantly activated kinase signaling pathways20 instead of a single oncogenic driver mutation, genomics-based analysis alone is most likely not sufficient to predict response to sunitinib21. A functional pathway analysis may be a more promising approach22,23. Proteins are the driving force of cellular function, including intracellular signaling and immune responses. Post-translational modifications, such as phosphorylation, have a major role in regulation of protein function and activity. (Phospho)proteomics based on liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) offers insight in aberrantly activated kinase signaling pathways and potential drug targets through the global analysis of phosphorylated proteins. This method has high potential for patient stratification and prediction of therapy response24-28. In particular, phosphotyrosine-(pTyr)-phosphoproteomics provides an opportunity for the identification of patient subgroups likely to benefit from TKI’s29. As only 1% of all protein phosphorylations occur on tyrosine residues30, enrichment of tyrosine phosphorylated peptides is necessary prior to LC-MS/MS. 4
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