Inhibiting Drivers of Non-mutational Drug Tolerance Is a Salvage Strategy for Targeted Melanoma Therapy.
Inhibiting Drivers of Non-mutational Drug Tolerance Is a Salvage Strategy for Targeted Melanoma Therapy.
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DOI：
10.1016/j.ccell.2016.02.003
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发表时间：
2016-03-14
期刊：
影响因子：
50.3
通讯作者：
Wellbrock C
中科院分区：
文献类型：
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作者：
Smith MP;Brunton H;Rowling EJ;Ferguson J;Arozarena I;Miskolczi Z;Lee JL;Girotti MR;Marais R;Levesque MP;Dummer R;Frederick DT;Flaherty KT;Cooper ZA;Wargo JA;Wellbrock C
一旦黑色素瘤进展并获得对丝裂原活化蛋白激酶（MAPK）靶向治疗的抗性，突变异质性就提出了一个重大挑战。因此，我们检查了获得性耐药发生之前的治疗阶段，并发现黑色素瘤生存癌基因MITF是早期非突变和可逆药物耐受状态的驱动因素，这是由PAX 3介导的MITF上调诱导的。药物重新定位筛选确定HIV 1蛋白酶抑制剂奈非那韦为PAX 3和MITF表达的有效抑制剂。奈非那韦使BRAF和NRAS突变型黑色素瘤细胞对MAPK通路抑制剂高度敏感。此外，奈非那韦对从MAPK抑制剂（MAPKi）治疗进展的患者中分离的BRAF和NRAS突变型黑色素瘤细胞以及BRAF/NRAS/PTEN突变型肿瘤有效。我们证明，抑制MAPKi诱导的药物耐受性的驱动因素可以改善目前靶向黑色素瘤治疗的方法。MITF是黑色素瘤中可逆的非突变药物耐受期的驱动因素。药物重新定位将甲磺酸奈非那韦鉴定为MITF表达的抑制剂奈非那韦使BRAF和NRAS突变黑色素瘤对MAPK抑制剂治疗敏感。发现PAX 3介导的MITF过表达是BRAF突变型黑色素瘤中MAPK途径抑制的可逆抗性机制，并鉴定了奈非那韦，其抑制该机制并不仅使BRAF突变型黑色素瘤细胞而且使BRAF和NRAS突变型黑色素瘤细胞对MAPK途径抑制剂敏感。
Once melanomas have progressed with acquired resistance to mitogen-activated protein kinase (MAPK)-targeted therapy, mutational heterogeneity presents a major challenge. We therefore examined the therapy phase before acquired resistance had developed and discovered the melanoma survival oncogene MITF as a driver of an early non-mutational and reversible drug-tolerance state, which is induced by PAX3-mediated upregulation of MITF. A drug-repositioning screen identified the HIV1-protease inhibitor nelfinavir as potent suppressor of PAX3 and MITF expression. Nelfinavir profoundly sensitizes BRAF and NRAS mutant melanoma cells to MAPK-pathway inhibitors. Moreover, nelfinavir is effective in BRAF and NRAS mutant melanoma cells isolated from patients progressed on MAPK inhibitor (MAPKi) therapy and in BRAF/NRAS/PTEN mutant tumors. We demonstrate that inhibiting a driver of MAPKi-induced drug tolerance could improve current approaches of targeted melanoma therapy. MITF is a driver of a reversible non-mutational drug-tolerance phase in melanoma Drug repositioning identifies nelfinavir mesylate as a suppressor of MITF expression Nelfinavir sensitizes BRAF and NRAS mutant melanoma to MAPK inhibitor treatment A nelfinavir combination therapy overcomes NRAS-driven acquired resistance Smith et al. discover PAX3-mediated overexpression of MITF as a reversible resistance mechanism to MAPK-pathway inhibition in BRAF mutant melanomas and identify nelfinavir, which inhibits this mechanism and sensitizes not only BRAF mutant but also BRAF and NRAS mutant melanoma cells to MAPK-pathway inhibitors.