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Immunoregulatory protein B7‐H3 promotes growth and decreases sensitivity to therapy in metastatic melanoma cells
Author(s) -
FlemKarlsen Karine,
Tekle Christina,
Andersson Yvonne,
Flatmark Kjersti,
Fodstad Øystein,
NunesXavier Caroline E.
Publication year - 2017
Publication title -
pigment cell and melanoma research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.618
H-Index - 105
eISSN - 1755-148X
pISSN - 1755-1471
DOI - 10.1111/pcmr.12599
Subject(s) - vemurafenib , dacarbazine , cancer research , melanoma , pi3k/akt/mtor pathway , protein kinase b , mek inhibitor , mapk/erk pathway , targeted therapy , metastasis , monoclonal antibody , medicine , kinase , biology , cancer , metastatic melanoma , antibody , immunology , signal transduction , microbiology and biotechnology
Summary B7‐H3 ( CD 276) 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 ( PLX 4032; BRAF inhibitor), binimetinib ( MEK ‐162; MEK inhibitor), everolimus ( RAD 001; 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 antiproliferative effect in melanoma cells, as well as in BRAF V 600E 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.