Transmembrane glycoprotein GPNMB is a candidate predictive biomarker and potentially a therapeutic target in metastatic renal cell carcinoma

Background: Metastatic renal cell carcinoma (mRCC) is a serious disease with adverse prognosis often treated with receptor tyrosine kinase inhibitors (TKI). However, approximately a half of mRCC patients do not profit from TKI, and there is no clinical molecular marker identifying these non-responders.

Methods: To address this issue, we performed a retrospective proteomic study on 53 mRCC tumors treated with TKI (30 non-responders vs. 23 responders) using next-generation, data independent acquisition mass spectrometry. To investigate the potential of key identified protein as an alternative therapeutic target, we knocked-out its expression using CRISPR/Cas9 and performed migration and invasion studies in 786-0 RCC cell line.

Results: 6183 protein groups (FDR 0.01) were consistently quantified in the proteomics dataset. Analysis of differential protein abundance identified 12 proteins associated with poor treatment response, of which 5 were successfully confirmed in a validation cohort (12 non-responders vs. 10 non-responders). Of these, transmembrane glycoprotein B (GPNMB) exhibited the best predictive value for treatment response (AUC=0.753, p=1.4.10-9), was associated with progression-free survival (HR=1.403, padj=0.0207) and trend of increased GPNMB levels was visible in an independent cohort (n=40) using immunohistochemistry. Comparison of parental and GPNMB-/- cells showed that GPNMB supports migration capacity of 786-0 cells in scratch (p=0.0073) and Transwell (p < 0.0001) assays, and also cell invasiveness in Transwell (p=0.0009) and 3D invasion (p < 0.0001) assays. Pathway analysis associated GPNMB deregulation with enrichment of INFLAMMATORY_RESPONSE pathway in both mRCC tissues and 786-0 cells.

Conclusions: Our data show that GPNMB has potential to serve as predictive biomarker of poor TKI response and hypothetically also as mRCC therapeutic target since GPNMB blockage might overcome TKI resistance.

Supported by Ministry of Health of the Czech Republic, grant nr. NV19-08-00250, all rights reserved. CIISB, Instruct-CZ Centre of Instruct-ERIC EU consortium, funded by MEYS CR infrastructure project LM2023042 and European Regional Development Fund-Project "UP CIISB" (No. CZ.02.1.01/0.0/0.0/18_046/0015974), is gratefully acknowledged for the financial support of the measurements at the CEITEC Proteomics Core Facility. Supported by the project National Institute for Cancer Research (Programme EXCELES, ID Project No. LX22NPO5102)— Funded by the European Union—Next Generation EU.