Issa Issa Ismail, Brøndum Rasmus Froberg, Due Hanne, Schmidt Linnéa, Bøgsted Martin, Dybkær Karen
Department of Haematology, Aalborg University Hospital, Aalborg 9000, Denmark.
Department of Clinical Medicine, Aalborg University, Aalborg 9000, Denmark.
Cancer Drug Resist. 2021 Mar 19;4(1):208-222. doi: 10.20517/cdr.2020.76. eCollection 2021.
: Bendamustine is primarily used for treatment of indolent lymphomas but has shown efficacy in some patients with diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (MM). Molecular-based patient stratification for identification of resistant patients, who will benefit from alternative treatments, is important. The aim of this study was to develop a resistance gene signature (REGS) from bendamustine dose-response assays in cultures of DLBCL and MM cell lines, enabling prediction of bendamustine response in DLBCL and MM patients. : Bendamustine response was determined in 14 DLBCL and 11 MM cell lines. Using baseline gene expression profiles and degree of growth inhibition after bendamustine exposure, a bendamustine REGS was developed and examined for the risk stratification potential in DLBCL ( = 971) and MM ( = 1,126) patients divided into prognostic subtypes. : Bendamustine resistance significantly correlated with resistance to cyclophosphamide in DLBCL and melphalan in MM cell lines. The bendamustine REGS showed significantly lower bendamustine resistance probabilities in DLBCL patients with GCB subtype tumors and in tumors of the differentiation dependent centrocyte and plasmablast subtypes. In MM patients, pre-BII classified tumors displayed high bendamustine resistance probabilities and the plasma cell subtype had lower bendamustine resistance probability than memory cells. Furthermore, tumors belonging to the 4p14, MAF, and D2 TC subclasses consistently displayed high bendamustine resistance probabilities. : Significant differences in predicted response to bendamustine were found in molecular subtypes of DLBCL and MM, encouraging validation in prospective bendamustine-treated cohorts with available gene expression profiles and follow-up data.
苯达莫司汀主要用于治疗惰性淋巴瘤，但在一些弥漫性大B细胞淋巴瘤（DLBCL）和多发性骨髓瘤（MM）患者中也显示出疗效。基于分子的患者分层以识别耐药患者（这些患者将从替代治疗中获益）很重要。本研究的目的是从DLBCL和MM细胞系培养物中的苯达莫司汀剂量反应试验中开发一种耐药基因特征（REGS），从而能够预测DLBCL和MM患者对苯达莫司汀的反应。在14个DLBCL细胞系和11个MM细胞系中测定了苯达莫司汀反应。利用基线基因表达谱和苯达莫司汀暴露后的生长抑制程度，开发了一种苯达莫司汀REGS，并在分为预后亚型的DLBCL（n = 971）和MM（n = 1,126）患者中检验其风险分层潜力。在DLBCL细胞系中，苯达莫司汀耐药与对环磷酰胺的耐药显著相关，在MM细胞系中与对美法仑的耐药显著相关。苯达莫司汀REGS显示，在具有生发中心B细胞（GCB）亚型肿瘤的DLBCL患者以及分化依赖中心细胞和浆母细胞亚型的肿瘤中，苯达莫司汀耐药概率显著较低。在MM患者中，前BII分类的肿瘤显示出高苯达莫司汀耐药概率，而浆细胞亚型的苯达莫司汀耐药概率低于记忆细胞。此外，属于4p14、MAF和D2 TC亚类的肿瘤始终显示出高苯达莫司汀耐药概率。在DLBCL和MM的分子亚型中发现了对苯达莫司汀预测反应的显著差异，这鼓励在具有可用基因表达谱和随访数据的前瞻性苯达莫司汀治疗队列中进行验证。
