PDF(Pubmed)
Abstract：
Multiple myeloma (MM) is a hematological malignancy characterized by an abnormal clonal proliferation of malignant plasma cells. Despite the introduction of novel agents that have significantly improved clinical outcome, most patients relapse and develop drug resistance. MM is characterized by genomic instability and a high level of replicative stress. In response to replicative and DNA damage stress, MM cells activate various DNA damage signaling pathways. In this study, we reported that high CHK1 and WEE1 expression is associated with poor outcome in independent cohorts of MM patients treated with high dose melphalan chemotherapy or anti-CD38 immunotherapy. Combined targeting of Chk1 and Wee1 demonstrates synergistic toxicities on MM cells and was associated with higher DNA double-strand break induction, as evidenced by an increased percentage of γH2AX positive cells subsequently leading to apoptosis. The therapeutic interest of Chk1/Wee1 inhibitors\' combination was validated on primary MM cells of patients. The toxicity was specific of MM cells since normal bone marrow cells were not significantly affected. Using deconvolution approach, MM patients with high CHK1 expression exhibited a significant lower percentage of NK cells whereas patients with high WEE1 expression displayed a significant higher percentage of regulatory T cells in the bone marrow. These data emphasize that MM cell adaptation to replicative stress through Wee1 and Chk1 upregulation may decrease the activation of the cell-intrinsic innate immune response. Our study suggests that association of Chk1 and Wee1 inhibitors may represent a promising therapeutic approach in high-risk MM patients characterized by high CHK1 and WEE1 expression.
摘要：
多发性骨髓瘤（MM）是一种血液恶性肿瘤，其特征是恶性浆细胞的异常克隆增殖。尽管引入了具有显著改善临床结果的新型药物,大多数患者复发并产生耐药性。MM的特征在于基因组不稳定性和高水平的复制应激。为了应对复制和DNA损伤应激，MM细胞激活各种DNA损伤信号通路。在这项研究中,我们报道,在接受高剂量美法仑化疗或抗CD38免疫治疗的独立MM患者队列中,高CHK1和WEE1表达与不良结局相关.Chk1和Wee1的联合靶向显示对MM细胞的协同毒性，并与更高的DNA双链断裂诱导相关，如随后导致细胞凋亡的γH2AX阳性细胞百分比增加所证明的。Chk1/Wee1抑制剂组合的治疗兴趣在患者的原代MM细胞上得到验证。由于正常骨髓细胞没有受到显著影响,因此毒性是MM细胞的特异性。使用反卷积方法，具有高CHK1表达的MM患者表现出显著较低的NK细胞百分比,而具有高WEE1表达的患者在骨髓中表现出显著较高的调节性T细胞百分比。这些数据强调MM细胞通过Wee1和Chk1上调对复制应激的适应可以降低细胞固有的先天免疫应答的激活。我们的研究表明，在以CHK1和WEE1高表达为特征的高危MM患者中，Chk1和Wee1抑制剂的联合可能是一种有希望的治疗方法。
