Activation of unfolded protein response overcomes Ibrutinib resistance in diffuse large B-cell lymphoma

• 作者: Xiao-tuan Zhang Xiao-bei Hu Han-lin Wang Wei-juan Kan Lei Xu Zhi-jia Wang Yu-qi Xiang Wen-biao Wu Bo Feng Jia-nan Li An-hui Gao Tian-cheng Dong Chun-mei Xia Yu-bo Zhou Jia Li
• 来源期刊: 中国药理学报（英文版）
• 年，卷（期）: 2021,（5）
• 所属期刊栏目: Chemotherapy
• 页码范围: 814-823
• 页数: 10页
• 语种: 英文

摘要

Diffuse large B-cell lymphoma (DLBCL) is the most widespread type of non-Hodgkin lymphoma (NHL).As the most aggressive form of the DLBCL,the activated B-cell-like (ABC) subtype is often resistant to standard chemotherapies.Bruton's tyrosine kinase (BTK) inhibitor ibrutinib provides a potential therapeutic approach for the DLBCL but fails to improve the outcome in the phase Ⅲ trial.In the current study,we investigated the molecular mechanisms underlying ibrutinib resistance and explored new combination therapy with ibrutinib.We generated an ibrutinib-resistant ABC-DLBCL cell line (OCI-ly10-1R) through continuous exposure to ibrutinib.Transcriptome analysis of the parental and ibrutinib-resistant cell lines revealed that the ibrutinib-resistant cells had significantly lower expression of the unfolded protein response (UPR) marker genes.Overexpression of one UPR branch-XBP1s greatly potentiated ibrutinib-induced apoptosis in both sensitive and resistant cells.The UPR inhibitor tauroursodeoxycholic acid (TUDCA) partially reduced the apoptotic rate induced by the ibrutinib in sensitive cells.The UPR activator 2-deoxy-D-glucose (2-DG) in combination with the ibrutinib triggered even greater cell growth inhibition,apoptosis,and stronger calcium (Ca2+) flux inhibition than either of the agents alone.A combination treatment of ibrutinib (15 mg.kg-1·d-1,po.) and 2-DG (500 mg/kg,po,b.i.d.) synergistically retarded tumor growth in NOD/SOD mice bearing OCI-ly10-1R xenograft.In addition,ibrutinib induced the UPR in the sensitive cell lines but not in the resistant cell lines of the DLBCL There was also a combined synergistic effect in the primary resistant DLBCL cell lines.Overall,our results suggest that targeting the UPR could be a potential combination strategy to overcome ibrutinib resistance in the DLBCL.