Pharmacogenomics and chemical library screens reveal a novel SCF(SKP2) inhibitor that overcomes Bortezomib resistance in multiple myeloma.
Pharmacogenomics and chemical library screens reveal a novel SCF(SKP2) inhibitor that overcomes Bortezomib resistance in multiple myeloma.
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DOI：
10.1038/leu.2016.258
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发表时间：
2017-03
期刊：
影响因子：
11.4
通讯作者：
Driscoll JJ
中科院分区：
文献类型：
--
作者：
Malek E;Abdel-Malek MA;Jagannathan S;Vad N;Karns R;Jegga AG;Broyl A;van Duin M;Sonneveld P;Cottini F;Anderson KC;Driscoll JJ
虽然蛋白酶体抑制剂（PI）硼替佐米（BTZ）对多发性骨髓瘤（MM）患者的临床获益仍未受到挑战，但剂量限制性毒性和耐药性限制了长期效用。E3泛素连接酶Skp 1-Cullin-1-Skp 2（SCFSkp 2）促进细胞周期抑制剂p27的蛋白酶体降解以增强肿瘤生长。SKP 2表达增加和p27水平降低在人类癌症中很常见，并且与治疗抗性相关。Cullin-1结合蛋白Commd 1和Skp 2结合蛋白Cks 1B可增加SCFSkp 2活性。在这里，我们观察到较高的CUL 1，COMMD 1和SKP 2 mRNA水平的CD 138+细胞从BTZ耐药MM患者分离。患者CD 138+细胞中较高的CUL 1、COMMD 1、SKP 2和CKS 1B mRNA水平与无进展生存期和总生存期降低相关。基因敲除CUL 1、COMMD 1或SKP 2破坏了SCFSkp 2复合物，稳定了p27，并增加了BTZ处理后膜联蛋白V阳性细胞的数量。化学文库筛选鉴定了一种新的化合物，命名为DT 204，其减少Skp 2与Cullin-1和Commd 1的结合，并协同增强BTZ诱导的细胞凋亡。DT 204与BTZ的共治疗克服了耐药性并减少了小鼠模型中骨髓瘤肿瘤的体内生长，具有存活益处。总之，这些结果为合理设计的药物组合提供了概念证明，这些药物组合包含SCFSkp 2抑制剂以治疗BTZ耐药疾病。
While clinical benefit of the proteasome inhibitor (PI) bortezomib (BTZ) for multiple myeloma (MM) patients remains unchallenged, dose-limiting toxicities and drug resistance limit the long-term utility. The E3 ubiquitin ligase Skp1–Cullin-1–Skp2 (SCFSkp2) promotes proteasomal degradation of the cell cycle inhibitor p27 to enhance tumor growth. Increased SKP2 expression and reduced p27 levels are frequent in human cancers and are associated with therapeutic resistance. SCFSkp2 activity is increased by the Cullin-1-binding protein Commd1 and the Skp2-binding protein Cks1B. Here we observed higher CUL1, COMMD1 and SKP2 mRNA levels in CD138+ cells isolated from BTZ-resistant MM patients. Higher CUL1, COMMD1, SKP2 and CKS1B mRNA levels in patient CD138+ cells correlated with decreased progression-free and overall survival. Genetic knockdown of CUL1, COMMD1 or SKP2 disrupted the SCFSkp2 complex, stabilized p27 and increased the number of annexin-V-positive cells after BTZ treatment. Chemical library screens identified a novel compound, designated DT204, that reduced Skp2 binding to Cullin-1 and Commd1, and synergistically enhanced BTZ-induced apoptosis. DT204 co-treatment with BTZ overcame drug resistance and reduced the in vivo growth of myeloma tumors in murine models with survival benefit. Taken together, the results provide proof of concept for rationally designed drug combinations that incorporate SCFSkp2 inhibitors to treat BTZ resistant disease.