2. Academic Validation
  3. Activation of unfolded protein response overcomes Ibrutinib resistance in diffuse large B-cell lymphoma

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

  • Acta Pharmacol Sin. 2021 May;42(5):814-823. doi: 10.1038/s41401-020-00505-3.
Xiao-Tuan Zhang 1 2,  Xiao-Bei Hu 1,  Han-Lin Wang 1 2 3,  Wei-Juan Kan 1,  Lei Xu 1 2 4,  Zhi-Jia Wang 1 5,  Yu-Qi Xiang 1 2 4,  Wen-Biao Wu 1 2 6,  Bo Feng 1 5,  Jia-Nan Li 1,  An-Hui Gao 1,  Tian-Cheng Dong 1,  Chun-Mei Xia 1,  Yu-Bo Zhou 7 8,  Jia Li 9 10 11
Affiliations

Affiliations

  • 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.
  • 7 National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
  • 8 University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China. [email protected].
  • 9 National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. [email protected].
  • 10 University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China. [email protected].
  • 11 School of Life Science and Technology, ShanghaiTech University, Shanghai, 200031, China. [email protected].
PMID: 32855532 DOI: 10.1038/s41401-020-00505-3
Abstract

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

2-DG; BTK inhibitor; DLBCL; TUDCA; UPR; ibrutinib resistance.

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