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

Metastatic renal cell carcinoma (mRCC) is a serious malignancy often treated with tyrosine kinase inhibitors (TKIs). However, approximately half of mRCC patients do not benefit from TKIs. To identify a molecular marker for these non-responders, we performed a retrospective proteomic study on a training ( n =53) and validation ( n =22) cohorts of TKIs-treated mRCC tumors. To evaluate the identified protein as a potential therapeutic target, we knocked out its expression using CRISPR/Cas9 and analyzed its effects on migration and invasion capacities, and cell proliferation of RCC-derived cells. Of 6,183 protein groups (FDR 0.01) quantified using proteomics, transmembrane glycoprotein B (GPNMB) had higher abundance in TKIs non-responding tumors, was associated with progression-free survival, and the trend of increased GPNMB levels was visible using immunohistochemistry ( n =40). Comparison of parental, GPNMB -/- cells and cells with GPNMB overexpression showed that GPNMB promotes the migration and invasion capacity of 786-0 cells as well as the proliferation of RCC-MF cells. Our data show that GPNMB has the potential to serve as a predictive biomarker of poor TKIs response and potentially as a therapeutic target in mRCC.