Theodosakis Nicholas, Micevic Goran, Langdon Casey G, Ventura Alessandra, Means Robert, Stern David F, Bosenberg Marcus W
Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA.
Department of Dermatology, Yale School of Medicine, New Haven, Connecticut, USA; Department of Dermatology, University of Rome Tor Vergata, Rome, Italy.
J Invest Dermatol. 2017 Oct;137(10):2187-2196. doi: 10.1016/j.jid.2016.12.033. Epub 2017 Jun 7.
Despite improvements in survival in metastatic melanoma with combined BRAF and mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor treatment, the overwhelming majority of patients eventually acquire resistance to both agents. Consequently, new targets for therapy in resistant tumors are currently being evaluated. Previous studies have identified p90 subfamily of ribosomal S6 kinase (p90RSK) family kinases as key factors for growth and proliferation, as well as protein synthesis via assembly of the 7-methyl-guanosine triphosphate cap-dependent translation complex. We sought to evaluate inhibitors of p90RSK family members: BI-D1870 and BRD7389, for their ability to inhibit both proliferation and protein synthesis in patient-derived melanoma cell lines with acquired resistance to combined treatment with the BRAF inhibitor vemurafenib and the mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor selumetinib. We found that the RSK inhibitors blocked cell proliferation and protein synthesis in multiple dual-resistant melanoma lines. In addition, single agent RSK inhibitor treatment was effective in drug-naïve lines, two of which are innately vemurafenib resistant. We also used Reverse Phase Protein Array screening to identify differential protein expression that correlates with BI-D1870 sensitivity, and identified prognostic biomarkers for survival in human melanoma patients. These findings establish p90RSK inhibition as a therapeutic strategy in treatment-resistant melanoma and provide insight into the mechanism of action.
尽管联合使用BRAF和丝裂原活化蛋白激酶/细胞外信号调节激酶抑制剂治疗转移性黑色素瘤可提高生存率，但绝大多数患者最终会对这两种药物产生耐药性。因此，目前正在评估耐药肿瘤的新治疗靶点。先前的研究已确定核糖体S6激酶（p90RSK）家族激酶的p90亚家族是生长、增殖以及通过7-甲基鸟苷三磷酸帽依赖性翻译复合体组装进行蛋白质合成的关键因素。我们试图评估p90RSK家族成员的抑制剂：BI-D1870和BRD7389，看它们对获得性耐药于BRAF抑制剂维莫非尼和丝裂原活化蛋白激酶/细胞外信号调节激酶抑制剂司美替尼联合治疗的患者来源黑色素瘤细胞系中增殖和蛋白质合成的抑制能力。我们发现RSK抑制剂可阻断多种双重耐药黑色素瘤细胞系中的细胞增殖和蛋白质合成。此外，单药RSK抑制剂治疗对未接受过药物治疗的细胞系有效，其中两个细胞系天然对维莫非尼耐药。我们还使用反向蛋白质阵列筛选来鉴定与BI-D18所敏感性相关的差异蛋白质表达，并确定人类黑色素瘤患者生存的预后生物标志物。这些发现确立了p90RSK抑制作为治疗耐药性黑色素瘤的一种治疗策略，并深入了解了其作用机制。
