Division of Hematology-Oncology, Mayo Clinic, Scottsdale, AZ 85259, USA.
Leuk Lymphoma. 2013 Apr;54(4):683-7. doi: 10.3109/10428194.2012.728597. Epub 2012 Sep 28.
Although several mechanisms have been proposed to explain the activity of thalidomide, lenalidomide and pomalidomide in multiple myeloma (MM), including demonstrable anti-angiogenic, anti-proliferative and immunomodulatory effects, the precise cellular targets and molecular mechanisms have only recently become clear. A landmark study recently identified cereblon (CRBN) as a primary target of thalidomide teratogenicity. Subsequently it was demonstrated that CRBN is also required for the anti-myeloma activity of thalidomide and related drugs, the so-called immune-modulatory drugs (IMiDs). Low CRBN expression was found to correlate with drug resistance in MM cell lines and primary MM cells. One of the downstream targets of CRBN identified is interferon regulatory factor 4 (IRF4), which is critical for myeloma cell survival and is down-regulated by IMiD treatment. CRBN is also implicated in several effects of IMiDs, such as down-regulation of tumor necrosis factor-α (TNF-α) and T cell immunomodulatory activity, demonstrating that the pleotropic actions of the IMiDs are initiated by binding to CRBN. Future dissection of CRBN downstream signaling will help to delineate the underlying mechanisms for IMiD action and eventually lead to development of new drugs with more specific anti-myeloma activities. It may also provide a biomarker to predict IMiD response and resistance.
虽然已经提出了几种机制来解释沙利度胺、来那度胺和泊马度胺在多发性骨髓瘤（MM）中的活性，包括可证明的抗血管生成、抗增殖和免疫调节作用，但精确的细胞靶点和分子机制最近才变得清晰。最近的一项里程碑式研究确定了 cereblon (CRBN) 是沙利度胺致畸性的主要靶点。随后表明，CRBN 也是沙利度胺和相关药物（所谓的免疫调节药物[IMiDs]）抗骨髓瘤活性所必需的。低 CRBN 表达与 MM 细胞系和原发性 MM 细胞中的药物耐药性相关。鉴定出的 CRBN 的下游靶标之一是干扰素调节因子 4 (IRF4)，它对骨髓瘤细胞的存活至关重要，并且受 IMiD 治疗下调。CRBN 还与 IMiDs 的几种作用有关，例如下调肿瘤坏死因子-α (TNF-α) 和 T 细胞免疫调节活性，表明 IMiD 的多效作用是通过与 CRBN 结合而引发的。对 CRBN 下游信号的进一步剖析将有助于阐明 IMiD 作用的潜在机制，并最终导致开发具有更特异抗骨髓瘤活性的新药。它还可能提供预测 IMiD 反应和耐药性的生物标志物。
