Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Lymphoma

Degradation of Bruton’s tyrosine kinase mutants by PROTACs for potential treatment of ibrutinib-resistant non-Hodgkin lymphomas

Leukemia volume 33, pages 2105–2110 (2019)Cite this article

Subjects

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL). In the United States and United Kingdom, the annual prevalence of DLBCL is as high as 0.08% [1]. The first-line clinical treatment for DLBCL is combined chemo-immunotherapy with a 5-year survival rate of around 58% for senior adults [2]. Mantle cell lymphoma (MCL) contributes to more than 6–8% of NHL worldwide [3]. Because of the t(11;14)(q13;q32) chromosomal translocation and upregulated expression of cyclin D1, malignant proliferation is commonly observed in MCL [4]. Unfortunately, there is no optimal therapy for MCL [5] and the 5-year survival rate for MCL patients in the United States is <50% [6]. These statistics highlight an urgent need for the development of more effective treatments for patients with DLBCL or MCL.

B-cell receptor (BCR) signaling is indispensable for the adhesion, survival, and growth of B cells. As an essential membrane proximal signal molecule in the BCR pathway, Bruton’s tyrosine kinase (BTK) plays a critical role in B-cell activation and proliferation [7]. In 2013, the BTK covalent inhibitor ibrutinib was approved by the Food and Drug Administration for the treatment of MCL. Additionally, activated B-cell-like (ABC)-DLBCL patients achieved remission after treatment with ibrutinib [8]. Unfortunately, drug-resistant tumor cells have been isolated from MCL patients during treatment with ibrutinib and the relapse-specific C481S missense BTK mutation contributes to this resistance [9]. In the growth inhibition of DLBCL, the BTK C481S mutant also resulted in resistance to ibrutinib [10].

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2

References

  1. Morton LM, Wang SS, Devesa SS, Hartge P, Weisenburger DD, Linet MS. Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001. Blood. 2006;107:265–76.

    Article  CAS  Google Scholar 

  2. Feugier P, van Hoof A, Sebban C, Solal-Celigny P, Bouabdallah R, Fermé C, et al. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the groupe d'Etude des lymphomes de l’adulte. J Clin Oncol. 2005;23:4117–26.

    Article  CAS  Google Scholar 

  3. Pérez-Galán P, Dreyling M, Wiestner A. Mantle cell lymphoma: biology, pathogenesis, and the molecular basis of treatment in the genomic era. Blood. 2011;117:26–38.

    Article  Google Scholar 

  4. Li JY, Gaillard F, Moreau A, Harousseau JL, Laboisse C, Milpied N, et al. Detection of translocation t(11;14)(q13; q32) in mantle cell lymphoma by fluorescence in situ hybridization. Am J Pathol. 1999;154:1449–52.

    Article  CAS  Google Scholar 

  5. Rajabi B, Sweetenham JW. Mantle cell lymphoma: observation to transplantation. Ther Adv Hematol. 2015;6:37–48.

    Article  CAS  Google Scholar 

  6. Herrmann A, Hoster E, Zwingers T, Brittinger G, Engelhard M, Meusers P, et al. Improvement of overall survival in advanced stage mantle cell lymphoma. J Clin Oncol. 2009;27:511–8.

    Article  Google Scholar 

  7. Wang ML, Rule S, Martin P, Goy A, Auer R, Kahl BS, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013;369:507–16.

    Article  CAS  Google Scholar 

  8. Wilson WH, Young RM, Schmitz R, Yang Y, Pittaluga S, Wright G, et al. Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nat Med. 2015;21:922–6.

    Article  CAS  Google Scholar 

  9. Chiron D, Di Liberto M, Martin P, Huang X, Sharman J, Blecua P, et al. Cell-cycle reprogramming for PI3K inhibition overrides a relapse-specific C481S BTK mutation revealed by longitudinal functional genomics in mantle cell lymphoma. Cancer Discov. 2014;4:1022–35.

    Article  CAS  Google Scholar 

  10. Sun YH, Zhao XW, Ding N, Gao HY, Wu Y, Yang YQ, et al. PROTAC-induced BTK degradation as a novel therapy for mutated BTK C481S induced ibrutinib-resistant B-cell malignancies. Cell Res. 2018;28:779–81.

    Article  CAS  Google Scholar 

  11. Sakamoto KM, Kim KB, Kumagai A, Mercurio F, Crews CM, Deshaies RJ. Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proc Natl Acad Sci USA. 2001;98:8554–9.

    Article  CAS  Google Scholar 

  12. Toure M, Crews CM. Small-molecule PROTACS: new approaches to protein degradation. Angew Chem Int Ed. 2016;55:1966–73.

    Article  CAS  Google Scholar 

  13. Dobrovolsky D, Wang ES, Morrow S, Leahy C, Faust T, Nowak RP, et al. Bruton’s tyrosine kinase degradation as a therapeutic strategy for cancer. Blood. 2019;133:952–61.

    Article  Google Scholar 

  14. Buhimschi AD, Armstrong HA, Toure M, Jaime-Figueroa S, Chen TL, Lehman AM, et al. Targeting the C481S ibrutinib-resistance mutation in Bruton’s tyrosine kinase using PROTAC-mediated degradation. Biochemistry. 2018;57:3564–75.

    Article  CAS  Google Scholar 

  15. Zorba A, Nguyen C, Xu Y, Starr J, Borzilleri K, Smith J, et al. Delineating the role of cooperativity in the design of potent PROTACs for BTK. Proc Natl Acad Sci USA. 2018;115:E7285–92.

    Article  Google Scholar 

  16. Hamasy A, Wang Q, Blomberg KEM, Mohammad DK, Yu L, Vihinen M, et al. Substitution scanning identifies a novel, catalytically active ibrutinib-resistant BTK cysteine 481 to threonine (C481T) variant. Leukemia. 2017;31:177–85.

    Article  CAS  Google Scholar 

  17. Furman RR, Cheng S, Lu P, Setty M, Perez AR, Guo A, et al. Ibrutinib resistance in chronic lymphocytic leukemia. N Engl J Med. 2014;370:2352–4.

    Article  CAS  Google Scholar 

  18. Liu TM, Woyach JA, Zhong Y, Lozanski A, Lozanski G, Dong S, et al. Hypermorphic mutation of phospholipase C, γ2 acquired in ibrutinib-resistant CLL confers BTK independency upon B-cell receptor activation. Blood. 2015;126:61–8.

    Article  CAS  Google Scholar 

  19. Cheng S, Guo A, Lu P, Ma J, Coleman M, Wang YL. Functional characterization of BTK C481S mutation that confers ibrutinib resistance: exploration of alternative kinase inhibitors. Leukemia. 2015;29:895–900.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by National Natural Science Foundation of China (#81573277, 81622042, and 81773567), National Major Scientific and Technological Special Project for “Significant New Drugs Development” (#SQ2017ZX095003), and Tsinghua University Initiative Scientific Research Program. This work was also financially supported by NSFC (No. 81670187) and Beijing Natural Science Foundation (No. 7172047).

Author information

Author notes

  1. These authors contributed equally: Yonghui Sun, Ning Ding, Yuqin Song

  2. These authors jointly supervised this work: Wanli Liu, Jun Zhu, Yu Rao

Authors and Affiliations

  1. MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing, 100084, P.R. China

    Yonghui Sun, Zimo Yang & Yu Rao

  2. Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Lymphoma, Peking University Cancer Hospital & Institute, No.52 Fucheng Road, Haidian District, Beijing, 100142, China

    Ning Ding, Yuqin Song & Jun Zhu

  3. MOE Key Laboratory of Protein Sciences, Center for Life Sciences, Institute for Immunology, School of Life Sciences, Beijing Key Lab for Immunological Research on Chronic Diseases, Tsinghua University, Beijing, 100084, China

    Wanli Liu

Authors
  1. Yonghui Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ning Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuqin Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zimo Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wanli Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jun Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yu Rao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Wanli Liu, Jun Zhu or Yu Rao.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sun, Y., Ding, N., Song, Y. et al. Degradation of Bruton’s tyrosine kinase mutants by PROTACs for potential treatment of ibrutinib-resistant non-Hodgkin lymphomas. Leukemia 33, 2105–2110 (2019). https://doi.org/10.1038/s41375-019-0440-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-019-0440-x

This article is cited by

Search

Advanced search

Quick links