Flem-Karlsen Karine, Tekle Christina, Andersson Yvonne, Flatmark Kjersti, Fodstad Øystein, Nunes-Xavier Caroline E
Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital Radiumhospitalet, Oslo, Norway.
Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
Pigment Cell Melanoma Res. 2017 Sep;30(5):467-476. doi: 10.1111/pcmr.12599. Epub 2017 Jul 4.
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 BRAF 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.
B7-H3（CD276）属于免疫调节蛋白的B7家族，与癌症进展和转移有关。在本研究中，我们发现B7-H3表达敲低的转移性黑色素瘤细胞增殖和糖酵解能力略有下降，并且对达卡巴嗪（DTIC）化疗以及靶向丝裂原活化蛋白激酶（MAPK）和AKT/mTOR通路的小分子抑制剂更敏感：维莫非尼（PLX4032；BRAF抑制剂）、比美替尼（MEK-162；MEK抑制剂）、依维莫司（RAD001；mTOR抑制剂）和曲西立滨（API-2；AKT抑制剂）。在存在抑制性B7-H3单克隆抗体的情况下，黑色素瘤细胞中观察到类似的效果，而在B7-H3过表达细胞中则观察到相反的情况。此外，将B7-H3抑制与小分子抑制剂联合使用可显著增强黑色素瘤细胞以及源自患者活检的BRAF突变细胞系中的抗增殖作用。我们的研究结果表明，靶向B7-H3可能是改善转移性黑色素瘤当前治疗的一种新选择。
