文章：

识别多发性骨髓瘤中来那度胺耐药通路，并通过cereblon替代、STAT3抑制或IRF4靶向实现再致敏

Identification of lenalidomide resistance pathways in myeloma and targeted resensitization using cereblon replacement, inhibition of STAT3 or targeting of IRF4

原文发布日期：2019-02-11

DOI: 10.1038/s41408-019-0173-0

类型: Article

开放获取: 是

英文摘要：

To understand immunomodulatory drug (IMiD) resistance in multiple myeloma (MM), we created isogenic human multiple myeloma cell lines (HMCLs) sensitive and resistant to lenalidomide, respectively. Four HMCLs were demonstrated to be resistant to all IMiDs including lenalidomide, pomalidomide, and CC-220, but not to Bortezomib. In three HMLCs (MM.1.SLenRes, KMS11LenRes and OPM2LenRes), CRBN abnormalities were found, including chromosomal deletion, point mutation, and low CRBN expression. The remaining HMCL, XG1LenRes, showed no changes in CRBN but exhibited CD147 upregulation and impaired IRF4 downregulation after lenalidomide treatment. Depletion of CD147 in XG1LenRes and three additional HMCLs had no significant impact on MM viability and lenalidomide response. Further analysis of XG1LenRes demonstrated increased IL6 expression and constitutive STAT3 activation. Inhibition of STAT3 with a selective compound (PB-1-102) re-sensitized XG1LenRes to lenalidomide. Since XG1LenRes harbors a truncated IRF4 that is not downregulated by lenalidomide, we targeted IRF4/MYC axis with a selective inhibitor of the bromodomain of CBP/EP300 (SGC-CBP30), which restored lenalidomide response in XG1LenRes. This strategy also appeared to be more broadly applicable as SGC-CBP30 could re-sensitize two resistant HMCLs with low but detectable CRBN expression to lenalidomide, suggesting that targeting CBP/E300 is a promising approach to restore IMiD sensitivity in MM with detectable CRBN expression.

摘要翻译： 

为理解多发性骨髓瘤（MM）中免疫调节药物（IMiD）的耐药机制，我们构建了分别对来那度胺敏感和耐药的同源人多发性骨髓瘤细胞系（HMCLs）。其中四种HMCLs被证明对所有IMiDs（包括来那度胺、泊马度胺和CC-220）均产生耐药，但对硼替佐米仍保持敏感。在三种HMCLs（MM.1.SLenRes、KMS11LenRes和OPM2LenRes）中发现了CRBN异常，包括染色体缺失、点突变和低CRBN表达。其余HMCL（XG1LenRes）虽未显示CRBN变化，但在来那度胺治疗后出现CD147上调和IRF4下调受损。在XG1LenRes及另外三种HMCLs中敲低CD147对MM细胞活力及来那度胺反应均无显著影响。对XG1LenRes的进一步分析显示其IL6表达增加并存在STAT3持续性激活。使用选择性化合物（PB-1-102）抑制STAT3可使XG1LenRes恢复对来那度胺的敏感性。由于XG1LenRes携带截短型IRF4且不受来那度胺下调，我们采用CBP/EP300溴结构域选择性抑制剂（SGC-CBP30）靶向IRF4/MYC轴，成功使XG1LenRes恢复对来那度胺的反应。该策略显示出更广泛的适用潜力——SGC-CBP30能使两种具有低水平但可检测CRBN表达的耐药HMCLs重新敏感化，表明靶向CBP/EP300是为具有可检测CRBN表达的MM恢复IMiD敏感性的有效方法。

原文链接：

Identification of lenalidomide resistance pathways in myeloma and targeted resensitization using cereblon replacement, inhibition of STAT3 or targeting of IRF4