Department of Dermatology, The Saarland University Hospital, D-66421 Homburg/Saar, Germany.
Cancer Cell. 2013 Jun 10;23(6):811-25. doi: 10.1016/j.ccr.2013.05.003.
Despite success with BRAFV600E inhibitors, therapeutic responses in patients with metastatic melanoma are short-lived because of the acquisition of drug resistance. We identified a mechanism of intrinsic multidrug resistance based on the survival of a tumor cell subpopulation. Treatment with various drugs, including cisplatin and vemurafenib, uniformly leads to enrichment of slow-cycling, long-term tumor-maintaining melanoma cells expressing the H3K4-demethylase JARID1B/KDM5B/PLU-1. Proteome-profiling revealed an upregulation in enzymes of mitochondrial oxidative-ATP-synthesis (oxidative phosphorylation) in this subpopulation. Inhibition of mitochondrial respiration blocked the emergence of the JARID1B(high) subpopulation and sensitized melanoma cells to therapy, independent of their genotype. Our findings support a two-tiered approach combining anticancer agents that eliminate rapidly proliferating melanoma cells with inhibitors of the drug-resistant slow-cycling subpopulation.
尽管 BRAFV600E 抑制剂取得了成功，但转移性黑色素瘤患者的治疗反应是短暂的，因为会产生耐药性。我们基于肿瘤细胞亚群的存活确定了一种内在多药耐药的机制。用各种药物（包括顺铂和vemurafenib）治疗会统一导致表达 H3K4 去甲基化酶 JARID1B/KDM5B/PLU-1 的慢周期、长期维持肿瘤的黑素瘤细胞的富集。蛋白质组分析显示，该亚群中线粒体氧化-ATP 合成（氧化磷酸化）的酶上调。抑制线粒体呼吸会阻止 JARID1B(高)亚群的出现，并使黑色素瘤细胞对治疗敏感，而与它们的基因型无关。我们的研究结果支持一种双重方法，结合使用消除快速增殖的黑色素瘤细胞的抗癌药物和抑制耐药性慢周期亚群的抑制剂。
