Lee Hans C, Wang Hua, Baladandayuthapani Veerabhadran, Lin Heather, He Jin, Jones Richard J, Kuiatse Isere, Gu Dongmin, Wang Zhiqiang, Ma Wencai, Lim John, O'Brien Sean, Keats Jonathan, Yang Jing, Davis Richard E, Orlowski Robert Z
The Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
The Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Br J Haematol. 2017 Apr;177(1):80-94. doi: 10.1111/bjh.14525.
Dysregulation of MYC is frequently implicated in both early and late myeloma progression events, yet its therapeutic targeting has remained a challenge. Among key MYC downstream targets is ribosomal biogenesis, enabling increases in protein translational capacity necessary to support the growth and self-renewal programmes of malignant cells. We therefore explored the selective targeting of ribosomal biogenesis with the small molecule RNA polymerase (pol) I inhibitor CX-5461 in myeloma. CX-5461 induced significant growth inhibition in wild-type (WT) and mutant TP53 myeloma cell lines and primary samples, in association with increases in downstream markers of apoptosis. Moreover, Pol I inhibition overcame adhesion-mediated drug resistance and resistance to conventional and novel agents. To probe the TP53-independent mechanisms of CX-5461, gene expression profiling was performed on isogenic TP53 WT and knockout cell lines and revealed reduction of MYC downstream targets. Mechanistic studies confirmed that CX-5461 rapidly suppressed both MYC protein and MYC mRNA levels. The latter was associated with an increased binding of the RNA-induced silencing complex (RISC) subunits TARBP2 and AGO2, the ribosomal protein RPL5, and MYC mRNA, resulting in increased MYC transcript degradation. Collectively, these studies provide a rationale for the clinical translation of CX-5461 as a novel therapeutic approach to target MYC in myeloma.
MYC失调常与骨髓瘤的早期和晚期进展事件相关，但对其进行治疗靶向一直是一项挑战。核糖体生物合成是MYC的关键下游靶点之一，它能提高蛋白质翻译能力，以支持恶性细胞的生长和自我更新程序。因此，我们探索了使用小分子RNA聚合酶（pol）I抑制剂CX-5461对骨髓瘤中的核糖体生物合成进行选择性靶向。CX-5461在野生型（WT）和突变型TP53骨髓瘤细胞系及原代样本中诱导了显著的生长抑制，并伴随着凋亡下游标志物的增加。此外，抑制Pol I克服了黏附介导的耐药性以及对传统和新型药物的耐药性。为了探究CX-5461不依赖TP53的作用机制，我们对同基因的TP53 WT和敲除细胞系进行了基因表达谱分析，结果显示MYC下游靶点减少。机制研究证实，CX-5461能迅速抑制MYC蛋白和MYC mRNA水平。后者与RNA诱导沉默复合体（RISC）亚基TARBP2和AGO2、核糖体蛋白RPL5与MYC mRNA的结合增加有关，从而导致MYC转录本降解增加。总的来说，这些研究为CX-5461作为一种靶向骨髓瘤中MYC的新型治疗方法的临床转化提供了理论依据。
