Abstract
In preclinical models, c-Met promotes survival of renal cancer cells through the regulation of programmed death-ligand 1 (PD-L1). However, this relationship in human clear cell renal cell carcinoma (ccRCC) is not well characterized. We evaluated c-Met expression in ccRCC patients using paired primary and metastatic samples and assessed the association with PD-L1 expression and other clinical features. Areas with predominant and highest Fuhrman nuclear grade (FNG) were selected. c-Met expression was evaluated by IHC using an anti-Met monoclonal antibody (MET4 Ab) and calculated by a combined score (CS, 0–300): intensity of c-Met staining (0–3) x % of positive cells (0–100). PD-L1 expression in tumor cells was previously assessed by IHC and PD-L1+ was defined as PD-L1 > 0% positive cells. Our cohort consisted of 45 pairs of primary and metastatic ccRCC samples. Overall, c-Met expression was higher in metastatic sites compared to primary sites (average c-Met CS: 55 vs. 28, p = 0.0003). Higher c-Met expression was associated with higher FNG (4 vs. 3) in primary tumors (average c-Met CS: 52 vs. 20, p = 0.04). c-Met expression was numerically greater in PD-L1+ vs. PD-L1- tumors. Higher c-Met expression in metastatic sites compared to primary tumors suggests that testing for biomarkers of response to c-Met inhibitors should be conducted in metastases. While higher c-Met expression in PD-L1+ tumors requires further investigation, it supports exploring these targets in combination clinical trials.
Highlights
The cell-surface receptor tyrosine kinase c-Met is encoded by the c-MET proto-oncogene and is involved in several key functions, including cell growth, cell differentiation, neo-vascularization, and tissue repair [1]. c-Met and its only known ligand, hepatocyte growth factor (HGF), have been implicated in tumor development, invasion, migration and angiogenesis in solid tumor malignancies, including renal cell carcinoma (RCC) [2, 3]
We demonstrate that in our cohort of clear cell renal cell carcinoma (ccRCC) samples, c-Met expression is significantly higher in corresponding metastatic sites compared to paired primary tissues
Given that the treatment landscape for metastatic RCC (mRCC) has expanded to include small-molecule inhibition of vascular endothelial growth factor receptor (VEGFR), MET, and AXL pathways [14,15,16], our findings are informative in that they suggest that testing for biomarkers of response to c-Met inhibitors should be www.impactjournals.com/oncotarget conducted in metastases
Summary
The cell-surface receptor tyrosine kinase c-Met is encoded by the c-MET proto-oncogene and is involved in several key functions, including cell growth, cell differentiation, neo-vascularization, and tissue repair [1]. c-Met and its only known ligand, hepatocyte growth factor (HGF), have been implicated in tumor development, invasion, migration and angiogenesis in solid tumor malignancies, including renal cell carcinoma (RCC) [2, 3]. In the metastatic RCC (mRCC) setting, c- Met expression appears to be associated with worse outcomes in a retrospective cohort of patients treated with sunitinib, an antiangiogenic agent against vascular endothelial growth factor receptor (VEGFR) [7]. C-Met and the tyrosine-kinase AXL can be upregulated in RCC and have been shown to play a possible role in the development of resistance to VEGFR inhibitors making these pathways rational targets for therapeutic trials [8,9,10,11,12,13]. Cabozantinib, an oral, smallmolecule inhibitor of VEGFR, MET, and AXL, improved overall survival compared to everolimus in previouslytreated patients with advanced RCC [14, 15]. With the expanding treatment armament and the likely importance of c-Met in controlling mRCC, the quest for an optimal model to assess for predictive biomarkers for c-Met inhibition has emerged
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