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

Xiao-tuan Zhang1,2, Xiao-bei Hu1, Han-lin Wang1,2,3, Wei-juan Kan1, Lei Xu1,2,4, Zhi-jia Wang1,5, Yu-qi Xiang1,2,4, Wen-biao Wu1,2,6, Bo Feng1,5, Jia-nan Li1, An-hui Gao1, Tian-cheng Dong1, Chun-mei Xia1, Yu-bo Zhou1,2, Jia Li1,2,4
1 National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
2 University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
3 School of pharmacy, Fudan University, Shanghai 201203, China
4 School of Life Science and Technology, ShanghaiTech University, Shanghai 200031, China
5 School of Pharmaceutical Science, Jiangnan University, Wuxi 214122, China
6 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China
Correspondence to: Yu-bo Zhou:, Jia Li:,
DOI: 10.1038/s41401-020-00505-3
Received: 24 February 2020
Accepted: 3 August 2020
Advance online: 27 August 2020


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-IR) 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/SCID mice bearing OCI-ly10-IR 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.
Keywords: DLBCL; BTK inhibitor; ibrutinib resistance; UPR; TUDCA; 2-DG

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