Transmembrane glycoprotein GPNMB is a potential marker of poor response of metastatic renal cell carcinoma to tyrosine kinase receptor inhibitor treatment
| Authors | |
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| Year of publication | 2023 |
| Type | Conference abstract |
| MU Faculty or unit | |
| Citation | |
| Description | Metastatic renal cell carcinoma (mRCC) represents a systemic disease with a very poor prognosis. A targeted therapy with receptor tyrosine kinase inhibitors (rTKI) has been used in the first-line treatment of mRCC patients with good or intermediate prognosis for many years. However, about half of the patients respond poorly or do not respond to this treatment, and there is no clinical marker identifying these non-responders. To understand the molecular mechanisms associated with a poor response to rTKI and to identify patients who would benefit from an alternate treatment (e.g. immunotherapy or clinical trial), we performed a retrospective proteomics study on 53 mRCC tumors treated with rTKI (23 responders/30 non-responders) using next-generation, data-independent acquisition (DIA) mass spectrometry with a consistent quantification of 5977 protein groups (FDR 0.01). Analysis of differential protein abundance identified a panel of 12 proteins associated with treatment response, of which 5 were successfully validated in an independent cohort of 22 mRCC tumors (10 responders /12 non-responders). Of these, transmembrane glycoprotein GPNMB exhibited the best predictive value (AUC.5=0.756, p=4.733.10 -10 ), was associated with the time to response (p=0.048), and the trend of increased GPNMB protein levels was visible in another independent cohort (n=40) using immunohistochemistry. To investigate the potential of GPNMB to serve as an alternative therapeutic target in mRCC, we knocked out its expression using CRISPR/Cas9 in 786-0 cell line derived from RCC. Comparison of parental and GPNMB -/- cells showed that higher GPNMB protein level supports migration capacity of RCC cells in the scratch assay (p=0.0073) and Transwell assay (p < 0.0001), and supports cell invasiveness in Transwell assay (p=0.0009) and 3D invasion assay (p < 0.0001). In summary, GPNMB has the potential to serve as a biomarker of a poor mRCC response to rTKI treatment and potentially also as a therapeutic target in mRCC non-responding to rTKI as an alternative to TKI and potentially immunotherapy treatment. |
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