文章：

缺乏BTK^C481S或CXCR4^WHIM样突变的华氏巨球蛋白血症细胞可通过上调Bcl-2和AKT获得对伊布替尼的耐药性，从而对venetoclax或MK2206治疗产生易感性

Waldenstrom macroglobulinemia cells devoid of BTK^C481S or CXCR4^WHIM-like mutations acquire resistance to ibrutinib through upregulation of Bcl-2 and AKT resulting in vulnerability towards venetoclax or MK2206 treatment

原文发布日期：2017-05-26

DOI: 10.1038/bcj.2017.40

类型: Original Article

开放获取: 是

英文摘要：

Although ibrutinib is highly effective in Waldenstrom macroglobulinemia (WM), no complete remissions in WM patients treated with ibrutinib have been reported to date. Moreover, ibrutinib-resistant disease is being steadily reported and is associated with dismal clinical outcome (overall survival of 2.9–3.1 months). To understand mechanisms of ibrutinib resistance in WM, we established ibrutinib-resistant in vitro models using validated WM cell lines. Characterization of these models revealed the absence of BTKC481S and CXCR4WHIM-like mutations. BTK-mediated signaling was found to be highly attenuated accompanied by a shift in PI3K/AKT and apoptosis regulation-associated genes/proteins. Cytotoxicity studies using the AKT inhibitor, MK2206±ibrutinib, and the Bcl-2-specific inhibitor, venetoclax±ibrutinib, demonstrated synergistic loss of cell viability when either MK22016 or venetoclax were used in combination with ibrutinib. Our findings demonstrate that induction of ibrutinib resistance in WM cells can arise independent of BTKC481S and CXCR4WHIM-like mutations and sustained pressure from ibrutinib appears to activate compensatory AKT signaling as well as reshuffling of Bcl-2 family proteins for maintenance of cell survival. Combination treatment demonstrated greater (and synergistic) antitumor effect and provides rationale for development of therapeutic strategies encompassing venetoclax+ibrutinib or PI3K/AKT inhibitors+ibrutinib in ibrutinib-resistant WM.

摘要翻译： 

尽管伊布替尼对华氏巨球蛋白血症（WM）疗效显著，但迄今为止尚未有WM患者经伊布替尼治疗后达到完全缓解的报道。此外，伊布替尼耐药病例的持续出现与不良临床结局密切相关（总生存期仅2.9-3.1个月）。为探究WM中伊布替尼的耐药机制，我们采用经过验证的WM细胞系建立了伊布替尼耐药体外模型。这些模型的表征分析显示不存在BTK^C481S和CXCR4^WHIM样突变。研究发现BTK介导的信号传导显著减弱，同时伴随PI3K/AKT通路及凋亡调控相关基因/蛋白的转变。使用AKT抑制剂MK2206（联合/不联合伊布替尼）和Bcl-2特异性抑制剂维奈克拉（联合/不联合伊布替尼）进行的细胞毒性研究表明，当MK2206或维奈克拉与伊布替尼联用时，可协同降低细胞活力。我们的研究结果表明，WM细胞中伊布替尼耐药性的产生可不依赖于BTK^C481S和CXCR4^WHIM样突变，而伊布替尼的持续作用压力会激活代偿性AKT信号传导，并引发Bcl-2家族蛋白的重组以维持细胞生存。联合治疗显示出更强（且具有协同作用）的抗肿瘤效果，这为开发维奈克拉+伊布替尼或PI3K/AKT抑制剂+伊布替尼联合方案治疗伊布替尼耐药型WM提供了理论依据。

原文链接：

Waldenstrom macroglobulinemia cells devoid of BTKC481S or CXCR4WHIM-like mutations acquire resistance to ibrutinib through upregulation of Bcl-2 and AKT resulting in vulnerability towards venetoclax or MK2206 treatment