State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao SAR, China.
State Key Laboratory of Urban Water Resource and Environment, School of Environment, Harbin Institute of Technology, Harbin, China.
J Cell Mol Med. 2021 Feb;25(4):1972-1981. doi: 10.1111/jcmm.15994. Epub 2020 Dec 30.
Melanoma is a very aggressive form of skin cancer. Although BRAF inhibitors have been utilized for melanoma therapy, advanced melanoma patients still face a low five-year survival rate. Recent studies have shown that CRAF can compensate for BRAF depletion via regulating DNA synthesis to remain melanoma proliferation. Hence, targeting CRAF either alone or in combination with other protein pathways is a potential avenue for melanoma therapy. Based on our previously reported CRAF-selective inhibitor for renal cancer therapy, we have herein discovered an analogue (complex 1) from the reported CRAF library suppresses melanoma cell proliferation and melanoma tumour growth in murine models of melanoma via blocking the S100B and RAF pathways. Intriguingly, we discovered that inhibiting BRAF together with S100B exerts a novel synergistic effect to significantly restore p53 transcription activity and inhibit melanoma cell proliferation, whereas blocking BRAF together with CRAF only had an additive effect. We envision that blocking the pan-RAF and S100B/p53 pathways might be a novel synergistic strategy for melanoma therapy and that complex 1 is a potential inhibitor against melanoma via blocking the pan-RAF and S100B pathways.
黑色素瘤是一种非常侵袭性的皮肤癌。尽管 BRAF 抑制剂已被用于黑色素瘤治疗，但晚期黑色素瘤患者的五年生存率仍然很低。最近的研究表明，CRAF 可以通过调节 DNA 合成来补偿 BRAF 的缺失，从而保持黑色素瘤的增殖。因此，靶向 CRAF 无论是单独靶向还是与其他蛋白通路联合靶向，都是黑色素瘤治疗的一个潜在途径。基于我们之前报道的用于肾癌治疗的 CRAF 选择性抑制剂，我们从报道的 CRAF 文库中发现了一种类似物（复合物 1），它通过阻断 S100B 和 RAF 通路，抑制黑色素瘤细胞增殖和黑色素瘤肿瘤生长在黑色素瘤的小鼠模型中。有趣的是，我们发现抑制 BRAF 与 S100B 一起发挥了新的协同作用，可显著恢复 p53 转录活性并抑制黑色素瘤细胞增殖，而阻断 BRAF 与 CRAF 一起仅具有相加作用。我们设想阻断泛 RAF 和 S100B/p53 通路可能是黑色素瘤治疗的一种新的协同策略，并且复合物 1 可能是一种通过阻断泛 RAF 和 S100B 通路来抑制黑色素瘤的潜在抑制剂。
