Neuropilin 1 and Neuropilin 2 gene invalidation or pharmacological inhibition reveals their relevance for the treatment of metastatic renal cell carcinoma

Abstract Background Despite the improvement of relapse-free survival mediated by anti-angiogenic drugs like sunitinib (Sutent®), or combinations with immunotherapy, metastatic clear cell Renal Cell Carcinoma (mccRCC) remain incurable. Hence, new relevant treatments are urgently needed. The VEGFs coreceptors, Neuropilins 1, 2 (NRP1, 2) expressed on several tumor cells including ccRCC. We analyzed role VEGFs/NRPs signaling in ccRCC aggressiveness and evaluated relevance to target this pathway. Methods correlated NRP1, levels patients’ using online available data base. Human mouse were knocked-out for NRP1 NRP2 genes a CRISPR/Cas9 method. number metabolically active was XTT assays. Migration ability determined wound closure experiments invasion Boyden chamber coated collagen. Production VEGFA VEGFC ELISA. Experimental generated immuno-competent/deficient mice. effects competitive inhibitor 2, NRPa-308, tested vitro vivo above-mentioned tests experimental NRPa-308 docking performed both NRPs. Results Knock-out inhibited metabolism migration stimulated expression VEGFC, respectively. presented higher affinity than NRP1. It decreased migration/invasion more efficiently commercially NRP EG00229. robust inhibition growth immunocompetent immunodeficient Such associated pro-tumoral factors. Analysis TCGA database showed that pathway, pathway correlates only patients. Conclusions Our study strongly suggests inhibiting NRPs is treatment mccRCC patients therapeutic impasses represents hit.