Skip to main content

Advertisement

SpringerLink
Log in

Resistance to the BCL-XL degrader DT2216 in T-cell acute lymphoblastic leukemia is rare and correlates with decreased BCL-XL proteolysis

  • Short Communication
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

The BCL-2 family of anti-apoptotic proteins, BCL-2, BCL-XL and MCL-1, can mediate survival of some types of cancer. DT2216 is a PROteolysis-TArgeting Chimera (PROTAC) that degrades BCL-XL specifically and is in phase 1 trials. We sought to define the frequency and mechanism of resistance to DT2216 in T-cell acute lymphoblastic leukemia (T-ALL) cell lines.

Methods

We measured cell survival and protein levels of BCL-XL, BCL-2, MCL-1 and the pro-apoptotic BIM in 13 distinct T-ALL cell lines after exposure to varying concentrations of DT2216.

Results

We identified concentrations of DT2216 which were cytotoxic to each T-ALL cell line.

These concentrations have no correlation with the initial protein levels of BCL-XL, BCL-2, MCL-1 or BIM in each cell line. However, there was a correlation between survival to DT2216 and the efficiency of degradation of BCL-XL by DT2216. Only one cell line, SUP-T1, had significant resistance to DT2216, defined as an IC50 above what is achievable in murine tumors in vivo.

Conclusion

Resistance to DT2216 is rare in a wide variety of T-ALL cells but when it occurs is correlated with decreased BCL-XL degradation. Resistance to DT2216 in T-ALL is not predicted by initial BCL-XL or BIM protein levels, or BCL-2 or MCL-1 levels before or after treatment. These data imply that a phase 2 clinical trial of DT2216 in T-ALL should be widely available and not limited to a subset of patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Data availability

All data generated or analyzed during this study are included in this published article and its supplementary information files.

References

  1. Kale J, Osterlund EJ, Andrews DW (2017) Bcl-2 family proteins: changing partners in the dance towards death. Cell Death Differ 25(1):65–80. https://doi.org/10.1038/cdd.2017.186

    Article  CAS  Google Scholar 

  2. Shamas-Din A, Kale J, Leber B, Andrews DW (2013) Mechanisms of action of bcl-2 family proteins. Cold Spring Harb Perspect Biol 5(4):a008714. https://doi.org/10.1101/cshperspect.a008714

    Article  CAS  Google Scholar 

  3. Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, Dayton BD, Ding H, Enschede SH, Fairbrother WJ, Huang DC, Hymowitz SG, Jin S, Khaw SL, Kovar PJ, Lam LT, Lee J, Maecker HL, Marsh KC, Elmore SW (2013) ABT-199, a potent and selective bcl-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med 19(2):202–208. https://doi.org/10.1038/nm.3048

    Article  CAS  Google Scholar 

  4. Zhang X, Liu X, Zhou D, Zheng G (2020) Targeting anti-apoptotic BCL-2 family proteins for cancer treatment. Future Med Chem 12(7):563–565. https://doi.org/10.4155/fmc-2020-0004

    Article  CAS  Google Scholar 

  5. Gandhi L, Camidge DR, Ribeiro de Oliveira M, Bonomi P, Gandara D, Khaira D, Hann CL, McKeegan EM, Litvinovich E, Hemken PM, Dive C, Enschede SH, Nolan C, Chiu YL, Busman T, Xiong H, Krivoshik AP, Humerickhouse R, Shapiro GI, Rudin CM (2011) Phase I study of navitoclax (ABT-263), a novel Bcl-2 family inhibitor, in patients with small-cell lung cancer and other solid tumors. J Clin Oncol 29(7):909–16. https://doi.org/10.1200/JCO.2010.31.6208

    Article  CAS  Google Scholar 

  6. He Y, Khan S, Huo Z, Lv D, Zhang X, Liu X, Yuan Y, Hromas R, Xu M, Zheng G, Zhou D (2020) Proteolysis targeting chimeras (protacs) are emerging therapeutics for hematologic malignancies. J Hematol Oncol 13(1):103–127. https://doi.org/10.1186/s13045-020-00924-z

    Article  Google Scholar 

  7. He Y, Koch R, Budamagunta V, Zhang P, Zhang X, Khan S, Thummuri D, Ortiz YT, Zhang X, Lv D, Wiegand JS, Li W, Palmer AC, Zheng G, Weinstock DM, Zhou D (2020) DT2216—a bcl-xl-specific degrader is highly active against bcl-xl-dependent T cell lymphomas. J Hematol Oncol 13(1):95–108. https://doi.org/10.1186/s13045-020-00928-9

    Article  CAS  Google Scholar 

  8. Khan S, Zhang X, Lv D, Zhang Q, Zhang P, Liu X, Thummuri D, Yuan Y, Wiegand J, Pei J, Zhang W, Sharma A, Mccurdy C, Kuruvilla V, Baran N, Ferrando A, Kim Y, Rogojina A, Zhou D (2019) A selective BCL-XL PROTAC degrader achieves safe and potent antitumor activity. Nat Med. https://doi.org/10.1038/s41591-019-0668-z

    Article  Google Scholar 

  9. Thummuri D, Khan S, Underwood PW, Zhang P, Wiegand J, Zhang X, Budamagunta V, Sobh A, Tagmount A, Loguinov A, Riner AN, Akki AS, Williamson E, Hromas R, Vulpe CD, Zheng G, Trevino JG, Zhou D (2022) Overcoming gemcitabine resistance in pancreatic cancer using the BCL-XL-specific degrader DT2216. Mol Cancer Ther 21(1):184–192. https://doi.org/10.1158/1535-7163.MCT-21-0474

    Article  CAS  Google Scholar 

  10. Khan S, Wiegand J, Zhang P, Hu W, Thummuri D, Budamagunta V, Hua N, Jin L, Allegra CJ, Kopetz SE, Zajac-Kaye M, Kaye FJ, Zheng G, Zhou D (2022) BCL-XL PROTAC degrader DT2216 synergizes with sotorasib in preclinical models of KRASG12C-mutated cancers. J Hematol Oncol 15(1):23. https://doi.org/10.1186/s13045-022-01241-3

    Article  CAS  Google Scholar 

  11. Békés M, Langley DR, Crews CM (2022) PROTAC targeted protein degraders: the past is prologue. Nat Rev Drug Discov 21:181–200. https://doi.org/10.1038/s41573-021-00371-6

    Article  CAS  Google Scholar 

  12. Gao H, Sun X, Rao Y (2020) PROTAC Technology: opportunities and challenges. ACS Med Chem Lett 11(30):237–240. https://doi.org/10.1021/acsmedchemlett.9b00597

    Article  CAS  Google Scholar 

  13. Ma A, Pena JC, Chang B, Margosian E, Davidson L, Alt FW, Thompson CB (1995) (1995) Bclx regulates the survival of double-positive thymocytes. Proc Natl Acad Sci USA 92(11):4763–4767. https://doi.org/10.1073/pnas.92.11.4763

    Article  CAS  Google Scholar 

  14. Chonghaile TN, Roderick JE, Glenfield C, Ryan J, Sallan SE, Silverman LB, Loh ML, Hunger SP, Wood B, DeAngelo DJ, Stone R, Harris M, Gutierrez A, Kelliher MA, Letai A (2014) Maturation stage of T-cell acute lymphoblastic leukemia determines BCL-2 versus BCL-XL dependence and sensitivity to ABT-199. Cancer Discov 4(9):1074–87. https://doi.org/10.1158/2159-8290.CD-14-0353

    Article  CAS  Google Scholar 

  15. Leung KT, Li KK, Sun SS, Chan PK, Ooi VE, Chiu LC (2008) Activation of the JNK pathway promotes phosphorylation and degradation of BimEL–a novel mechanism of chemoresistance in T-cell acute lymphoblastic leukemia. Carcinogenesis 29(3):544–51. https://doi.org/10.1093/carcin/bgm294

    Article  CAS  Google Scholar 

  16. Kolb R, De U, Khan S et al (2021) Proteolysis-targeting chimera against BCL-XL destroys tumor-infiltrating regulatory T cells. Nat Commun 12:1281. https://doi.org/10.1038/s41467-021-21573-x

    Article  CAS  Google Scholar 

  17. Koch R, Christie AL, Crombie JL, Palmer AC, Plana D, Shigemori K, Morrow SN, Van Scoyk A, Wu W, Brem EA, Secrist JP, Drew L, Schuller AG, Cidado J, Letai A, Weinstock DM (2019) Biomarker-driven strategy for MCL1 inhibition in T-cell lymphomas. Blood 133(6):566–575. https://doi.org/10.1182/blood-2018-07-865527

    Article  CAS  Google Scholar 

  18. Follini E, Marchesini M, Roti G (2019) Strategies to overcome resistance mechanisms in T-cell acute lymphoblastic leukemia. Int J Mol Sci 20(12):3021. https://doi.org/10.3390/ijms20123021

    Article  CAS  Google Scholar 

  19. Beesley A, Palmer ML, Ford J et al (2016) Authenticity and drug resistance in a panel of acute lymphoblastic leukaemia cell lines. Br J Cancer 95:1537–1544. https://doi.org/10.1038/sj.bjc.6603447

    Article  CAS  Google Scholar 

  20. Raetz EA, Teachey DT (2016) T-cell acute lymphoblastic leukemia. Hematology 2016(1):580–588. https://doi.org/10.1182/asheducation-2016.1.580

    Article  Google Scholar 

  21. Goossens S, Radaelli E, Blanchet O et al (2015) ZEB2 drives immature T-cell lymphoblastic leukaemia development via enhanced tumour-initiating potential and IL-7 receptor signalling. Nat Commun 6:5794. https://doi.org/10.1038/ncomms6794

    Article  CAS  Google Scholar 

  22. Lv D, Pal P, Liu X et al (2021) Development of a BCL-xL and BCL-2 dual degrader with improved anti-leukemic activity. Nat Commun 12:6896. https://doi.org/10.1038/s41467-021-27210-x

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Funding from US National Institutes of Health (NIH) grant R01 CA242003 (D.Z. and G.Z.), RO1 CA205224 (R.H.) and the Cancer Prevention of Research Institute of Texas Individual Investigator grant RP220269.

Author information

Authors and Affiliations

  1. Division of Hematology and Medical Oncology, Department of Medicine and the Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA

    Arunima Jaiswal, Aruna Jaiswal, Elizabeth A. Williamson & Robert Hromas

  2. Division of Biostatistics, Department of Population Health Science, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA

    Jonathon Gelfond

  3. Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA

    Guangrong Zheng

  4. Center for Innovative Drug Development and the Department of Biochemistry and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA

    Daohong Zhou

Authors
  1. Arunima Jaiswal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aruna Jaiswal
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Elizabeth A. Williamson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jonathon Gelfond
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Guangrong Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Daohong Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Robert Hromas
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Arunima Jaiswal designed and performed experiments, Aruna Jaiswal and Elizabeth Williamson supervised experiments and edited the manuscript, Jonathon Gelfond performed the statistical analysis, Guangrong Zheng and Daohong Zhou designed experiments and edited the manuscript and Robert Hromas designed and supervised experiments and edited the manuscript.

Corresponding author

Correspondence to Robert Hromas.

Ethics declarations

Conflict of interest

G.Z. and D.Z. hold patents for use of BCL-XL PROTACs as senolytic and antitumor agents. G.Z., D.Z., and R.H. have equity in Dialectic Therapeutics, which owns the license for DT2216.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 3770 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jaiswal, A., Jaiswal, A., Williamson, E.A. et al. Resistance to the BCL-XL degrader DT2216 in T-cell acute lymphoblastic leukemia is rare and correlates with decreased BCL-XL proteolysis. Cancer Chemother Pharmacol 91, 89–95 (2023). https://doi.org/10.1007/s00280-022-04490-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-022-04490-8

Keywords

Search

Navigation