Transgelin Contributes to a Poor Response of Metastatic Renal Cell Carcinoma to Sunitinib Treatment.

Pavla Bouchalova,Pavel Bouchal,Jindrich Beranek,Jan Podhorec,Alexandr Poprach,David Potesil,Petr Lapcik

doi:10.3390/biomedicines9091145

Pavla Bouchalova, Pavel Bouchal + Show 5 more

Open Access

https://doi.org/10.3390/biomedicines9091145

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Abstract

Renal cell carcinoma (RCC) represents about 2–3% of all cancers with over 400,000 new cases per year. Sunitinib, a vascular endothelial growth factor tyrosine kinase receptor inhibitor, has been used mainly for first-line treatment of metastatic clear-cell RCC with good or intermediate prognosis. However, about one-third of metastatic RCC patients do not respond to sunitinib, leading to disease progression. Here, we aim to find and characterize proteins associated with poor sunitinib response in a pilot proteomics study. Sixteen RCC tumors from patients responding (8) vs. non-responding (8) to sunitinib 3 months after treatment initiation were analyzed using data-independent acquisition mass spectrometry, together with their adjacent non-cancerous tissues. Proteomics analysis quantified 1996 protein groups (FDR = 0.01) and revealed 27 proteins deregulated between tumors non-responding vs. responding to sunitinib, representing a pattern of deregulated proteins potentially contributing to sunitinib resistance. Gene set enrichment analysis showed an up-regulation of epithelial-to-mesenchymal transition with transgelin as one of the most significantly abundant proteins. Transgelin expression was silenced by CRISPR/Cas9 and RNA interference, and the cells with reduced transgelin level exhibited significantly slower proliferation. Our data indicate that transgelin is an essential protein supporting RCC cell proliferation, which could contribute to intrinsic sunitinib resistance.

Highlights

Renal cell carcinoma (RCC) represents about 2–3% of all cancers with over 400,000 new cases per year
To obtain quantitative protein-level data from the data-independent acquisition mass spectrometry (DIA-Mass Spectrometry (MS)) dataset, we first generated a spectral library based on triplicate measurements of pooled aliquots of all samples from both tumor and normal tissues from patients responding vs. non-responding to sunitinib treatment in data-dependent acquisition mode
The library was used for the extraction of quantitative data from the DIA-MS dataset of individually measured tumor tissue samples of eight sunitinib responders (R), eight sunitinib nonresponders (NR), and 16 paired adjacent non-tumor (N) tissues

Summary

Introduction

Renal cell carcinoma (RCC) represents about 2–3% of all cancers with over 400,000 new cases per year. A vascular endothelial growth factor tyrosine kinase receptor inhibitor, has been used mainly for first-line treatment of metastatic clear-cell RCC with good or intermediate prognosis. Vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKI) have been drugs of the first choice for years, namely in the firstline treatment of patients with good or intermediate risk according to Memorial Sloane. Anti-programmed death (PD1)/programmed death-ligand 1 (PD-L1) immunotherapeutic monoclonal antibodies and mammalian target of rapamycin (mTOR) inhibitors are being used for mccRCC treatment as well. These three therapeutic modes complement each other in mRCC management, especially if the patient does not respond to the selected treatment mode [6]

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