Immunoregulatory Protein B7-H3 Promotes Growth and Decreases Sensitivity to Therapy in Metastatic Melanoma Cells

Summary

B7-H3 (CD276) belongs to the B7-family of immunoregulatory proteins, and has been implicated in cancer progression and metastasis. In this study, we found that metastatic melanoma cells with knockdown expression of B7-H3 showed modest decrease in proliferation and glycolytic capacity, and were more sensitive to dacarbazine (DTIC) chemotherapy and small-molecule inhibitors targeting MAP kinase (MAPK)- and AKT/mTOR-pathways: vemurafenib (PLX4032; BRAF inhibitor), binimetinib (MEK-162; MEK inhibitor), everolimus (RAD001; mTOR inhibitor) and triciribidine (API-2; AKT inhibitor). Similar effects were observed in melanoma cells in the presence of an inhibitory B7-H3 monoclonal antibody, while the opposite was seen in B7-H3 overexpressing cells. Further, combining B7-H3 inhibition with small molecule inhibitors resulted in significantly increased anti-proliferative effect in melanoma cells, as well as in BRAF^V600E mutated cell lines derived from patient biopsies. Our findings indicate that targeting B7-H3 may be a novel alternative to improve current therapy of metastatic melanoma.

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