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...

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Bibliographic Details
Published in:Pigment cell and melanoma research 2017-09, Vol.30 (5), p.467-476
Main Authors: Flem‐Karlsen, Karine, Tekle, Christina, Andersson, Yvonne, Flatmark, Kjersti, Fodstad, Øystein, Nunes‐Xavier, Caroline E.
Format: Article
Language:English
Subjects:
AKT protein
AKT/mTOR inhibitors
B7 antigen
B7 Antigens - metabolism
B7‐H3/CD276
Benzimidazoles - pharmacology
Benzimidazoles - therapeutic use
Biotechnology
Cancer
Cell Line, Tumor
Cell proliferation
Cell Proliferation - drug effects
Chemotherapy
Dacarbazine
Dacarbazine - pharmacology
Dacarbazine - therapeutic use
Everolimus - pharmacology
Everolimus - therapeutic use
Gene Knockdown Techniques
Glycolysis
Humans
Immunoregulation
Indoles - pharmacology
Indoles - therapeutic use
Inhibitors
MAP kinase
MAPK
Melanoma
Melanoma - drug therapy
Melanoma - genetics
Melanoma - pathology
Metastases
Metastasis
Molecular Targeted Therapy
Monoclonal antibodies
Mutation - genetics
Neoplasm Metastasis
Protein Kinase Inhibitors - pharmacology
Protein Kinase Inhibitors - therapeutic use
Proteins
Sulfonamides - pharmacology
Sulfonamides - therapeutic use
targeted therapy
TOR protein
vemurafenib
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Summary: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 antiproliferative effect in melanoma cells, as well as in BRAFV600E 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.
ISSN:1755-1471
1755-148X
DOI:10.1111/pcmr.12599