Kinomic profiling to predict sunitinib response of patients with metastasized clear cell Renal Cell Carcinoma

作者：Jeannette Oosterwijk‐Wakka, Liesbeth Houkes, Loes F.M. van der Zanden, Lambertus A. Kiemeney, Kerstin Junker, Anne Y. Warren, Tim Eisen, Ulrich Jaehde, Marius T. Radu, Rob Ruijtenbeek, Egbert Oosterwijk · 发表于：Neoplasia · 年份：2024 · DOI：10.1016/j.neo.2024.101108 · 被引用次数：3 · 研究领域：Renal cell carcinoma treatment、Advanced Proteomics Techniques and Applications、Advanced Biosensing Techniques and Applications

INTRODUCTION: Treatment with Sunitinib, a potent multitargeted receptor tyrosine kinase inhibitor (TKI) has increased the progression-free survival (PFS) and overall-survival (OS) of patients with metastasized renal cell carcinoma (mRCC). With modest OS improvement and variable response and toxicity predictive and/or prognostic biomarkers are needed to personalize patient management: Prediction of individual TKI therapy response and resistance will increase successful treatment outcome while reducing unnecessary drug use and expense. The aim of this study was to investigate whether kinase activity analysis can predict sunitinib response and/or toxicity using tissue samples obtained from primary clear cell RCC (ccRCC) from a cohort of clinically annotated patients with mRCC receiving sunitinib as first-line treatment. MATERIALS AND METHODS: EuroTARGET partners collected ccRCC and matched normal kidney tissue samples immediately after surgery, snap-frozen and stored at -80°C until use. Phosphotyrosine-activity profiling was performed using PamChip® peptide microarrays (144 peptides derived from known phosphorylation sites in Protein Tyrosine Kinase substrates) of lysed tissue samples (5 µg protein input) of 163 mRCC patients. Evolve software Was used to analyze kinome profiles and Bionavigator was used for unsupervised and supervised clustering. The kinexus kinase predictor (www.phosphonet.ca) was used to analyze the peptide lists within the clusters. RESULTS: Kinome data was a...