Skip to main content
SpringerLink
Log in

Combining Ibrutinib with Chk1 Inhibitors Synergistically Targets Mantle Cell Lymphoma Cell Lines

  • Original Research Article
  • Published:
Targeted Oncology Aims and scope Submit manuscript

Abstract

Background

Mantle cell lymphoma (MCL) is an aggressive B cell lymphoma with an unfavorable clinical course. Besides deregulation of the cell cycle, B cell receptor (BCR) signaling, essential for MCL proliferation and survival, is also often deregulated due to constitutive activation of Bruton’s tyrosine kinase (BTK). The BTK inhibitor ibrutinib has been approved as a therapy for refractory MCL, and while it shows some clinical activity, patients frequently develop primary or secondary ibrutinib resistance and have very poor outcomes after relapsing following ibrutinib treatment.

Objective

To overcome ibrutinib resistance, new therapeutic approaches are needed. As checkpoint kinase 1 (Chk1) inhibitors have recently been shown to be effective as single agents in MCL, we assessed the combination of ibrutinib with Chk1 inhibitors.

Methods

We examined the activity of ibrutinib combined with the Chk1 inhibitor PF-00477736 in eight MCL cell lines and analyzed underlying cellular and molecular effects.

Results

The combination was synergistic in all tested cell lines through different mechanisms. The treatment induced apoptosis in ibrutinib-sensitive cell lines, while in ibrutinib-resistant cells the effect was mainly cytostatic and occurred at micromolar concentrations of ibrutinib.

Conclusions

The pharmacological approach of simultaneously targeting cell cycle checkpoints (by Chk1 inhibitors) and pro-survival pathways (by ibrutinib) might offer a promising new therapeutic strategy for MCL 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
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Vogt N, Dai B, Erdmann T, Berdel WE, Lenz G. The molecular pathogenesis of mantle cell lymphoma. Leuk Lymphoma. 2017;58(7):1530–7.

    Article  CAS  PubMed  Google Scholar 

  2. Dreyling MH, Bullinger L, Ott G, Stilgenbauer S, Muller-Hermelink HK, Bentz M, et al. Alterations of the cyclin D1/p16-pRB pathway in mantle cell lymphoma. Cancer Res. 1997;57(20):4608–14.

    CAS  PubMed  Google Scholar 

  3. Quintanilla-Martinez L, Davies-Hill T, Fend F, Calzada-Wack J, Sorbara L, Campo E, et al. Sequestration of p27Kip1 protein by cyclin D1 in typical and blastic variants of mantle cell lymphoma (MCL): implications for pathogenesis. Blood. 2003;101(8):3181–7.

    Article  CAS  PubMed  Google Scholar 

  4. Camacho E, Hernandez L, Hernandez S, Tort F, Bellosillo B, Bea S, et al. ATM gene inactivation in mantle cell lymphoma mainly occurs by truncating mutations and missense mutations involving the phosphatidylinositol-3 kinase domain and is associated with increasing numbers of chromosomal imbalances. Blood. 2002;99(1):238–44.

    Article  CAS  PubMed  Google Scholar 

  5. Bea S, Ribas M, Hernandez JM, Bosch F, Pinyol M, Hernandez L, et al. Increased number of chromosomal imbalances and high-level DNA amplifications in mantle cell lymphoma are associated with blastoid variants. Blood. 1999;93(12):4365–74.

    CAS  PubMed  Google Scholar 

  6. Campo E, Rule S. Mantle cell lymphoma: evolving management strategies. Blood. 2015;125(1):48–55.

    Article  CAS  PubMed  Google Scholar 

  7. Saba NS, Liu D, Herman SE, Underbayev C, Tian X, Behrend D, et al. Pathogenic role of B-cell receptor signaling and canonical NF-kappaB activation in mantle cell lymphoma. Blood. 2016;128(1):82–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Baran-Marszak F, Boukhiar M, Harel S, Laguillier C, Roger C, Gressin R, et al. Constitutive and B-cell receptor-induced activation of STAT3 are important signaling pathways targeted by bortezomib in leukemic mantle cell lymphoma. Haematologica. 2010;95(11):1865–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 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(6):507–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Zhang SQ, Smith SM, Zhang SY, Lynn Wang Y. Mechanisms of ibrutinib resistance in chronic lymphocytic leukaemia and non-Hodgkin lymphoma. Br J Haematol. 2015;170(4):445–56.

    Article  CAS  PubMed  Google Scholar 

  11. Colomer D, Campo E. Unlocking new therapeutic targets and resistance mechanisms in mantle cell lymphoma. Cancer Cell. 2014;25(1):7–9.

    Article  CAS  PubMed  Google Scholar 

  12. 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(9):1022–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Rahal R, Frick M, Romero R, Korn JM, Kridel R, Chan FC, et al. Pharmacological and genomic profiling identifies NF-kappaB-targeted treatment strategies for mantle cell lymphoma. Nat Med. 2014;20(1):87–92.

    Article  CAS  PubMed  Google Scholar 

  14. Chila R, Basana A, Lupi M, Guffanti F, Gaudio E, Rinaldi A, et al. Combined inhibition of Chk1 and Wee1 as a new therapeutic strategy for mantle cell lymphoma. Oncotarget. 2015;6(5):3394–408.

    Article  PubMed  Google Scholar 

  15. Restelli V, Chila R, Lupi M, Rinaldi A, Kwee I, Bertoni F, et al. Characterization of a mantle cell lymphoma cell line resistant to the Chk1 inhibitor PF-00477736. Oncotarget. 2015;6(35):37229–40.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Carrassa L, Chila R, Lupi M, Ricci F, Celenza C, Mazzoletti M, et al. Combined inhibition of Chk1 and Wee1: in vitro synergistic effect translates to tumor growth inhibition in vivo. Cell Cycle. 2012;11(13):2507–17.

    Article  CAS  PubMed  Google Scholar 

  17. Carrassa L, Sanchez Y, Erba E, Damia G. U2OS cells lacking Chk1 undergo aberrant mitosis and fail to activate the spindle checkpoint. J Cell Mol Med. 2009;13(8A):1565–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ubezio P. Microcomputer experience in analysis of flow cytometric DNA distributions. Comput Programs Biomed. 1985;19(2-3):159–66.

    Article  CAS  PubMed  Google Scholar 

  19. Honigberg LA, Smith AM, Sirisawad M, Verner E, Loury D, Chang B, et al. The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy. Proc Natl Acad Sci U S A. 2010;107(29):13075–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Leung-Pineda V, Ryan CE, Piwnica-Worms H. Phosphorylation of Chk1 by ATR is antagonized by a Chk1-regulated protein phosphatase 2A circuit. Mol Cell Biol. 2006;26(20):7529–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Goy A. Mantle cell lymphoma: is it time for a new treatment paradigm? Hematol Oncol Clin North Am. 2016;30(6):1345–70.

    Article  PubMed  Google Scholar 

  22. Inamdar AA, Goy A, Ayoub NM, Attia C, Oton L, Taruvai V, et al. Mantle cell lymphoma in the era of precision medicine-diagnosis, biomarkers and therapeutic agents. Oncotarget. 2016;7(30):48692–731.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Tucker D, Rule S. Novel agents in mantle cell lymphoma. Expert Rev Anticancer Ther. 2017;17(6):491–506.

    Article  CAS  PubMed  Google Scholar 

  24. Cheah CY, Chihara D, Romaguera JE, Fowler NH, Seymour JF, Hagemeister FB, et al. Patients with mantle cell lymphoma failing ibrutinib are unlikely to respond to salvage chemotherapy and have poor outcomes. Ann Oncol. 2015;26(6):1175–9.

    Article  CAS  PubMed  Google Scholar 

  25. Martin P, Maddocks K, Leonard JP, Ruan J, Goy A, Wagner-Johnston N, et al. Postibrutinib outcomes in patients with mantle cell lymphoma. Blood. 2016;127(12):1559–63.

    Article  CAS  PubMed  Google Scholar 

  26. Marostica E, Sukbuntherng J, Loury D, de Jong J, de Trixhe XW, Vermeulen A, et al. Population pharmacokinetic model of ibrutinib, a Bruton tyrosine kinase inhibitor, in patients with B cell malignancies. Cancer Chemother Pharmacol. 2015;75(1):111–21.

    Article  CAS  PubMed  Google Scholar 

  27. Wuerzberger-Davis SM, Chang PY, Berchtold C, Miyamoto S. Enhanced G2-M arrest by nuclear factor-{kappa}B-dependent p21waf1/cip1 induction. Mol Cancer Res. 2005;3(6):345–53.

    Article  CAS  PubMed  Google Scholar 

  28. Zheng X, Ding N, Song Y, Feng L, Zhu J. Different sensitivity of germinal center B cell-like diffuse large B cell lymphoma cells towards ibrutinib treatment. Cancer Cell Int. 2014;14(1):32.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Tang D, Wu D, Hirao A, Lahti JM, Liu L, Mazza B, et al. ERK activation mediates cell cycle arrest and apoptosis after DNA damage independently of p53. J Biol Chem. 2002;277(15):12710–7.

    Article  CAS  PubMed  Google Scholar 

  30. Cagnol S, Chambard JC. ERK and cell death: mechanisms of ERK-induced cell death--apoptosis, autophagy and senescence. FEBS J. 2010;277(1):2–21.

    Article  CAS  PubMed  Google Scholar 

  31. Rocha S, Garrett MD, Campbell KJ, Schumm K, Perkins ND. Regulation of NF-kappaB and p53 through activation of ATR and Chk1 by the ARF tumour suppressor. EMBO J. 2005;24(6):1157–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We thank J.D. Baggott who kindly edited the paper. This work is dedicated to the memory of Eugenio and Angela Filice.

Author information

Authors and Affiliations

  1. Laboratory of Molecular Pharmacology and Laboratory of Cancer Pharmacology, Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche “Mario Negri” (IRFMN), via La Masa 19, 20156, Milan, Italy

    Valentina Restelli, Monica Lupi, Micaela Vagni, Rosaria Chilà, Giovanna Damia & Laura Carrassa

  2. Institute of Oncology Research (IOR), Università della Svizzera Italiana (USI), Bellinzona, Switzerland

    Francesco Bertoni

  3. Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland

    Francesco Bertoni

Authors
  1. Valentina Restelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Monica Lupi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Micaela Vagni
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rosaria Chilà
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Francesco Bertoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Giovanna Damia
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Laura Carrassa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Giovanna Damia or Laura Carrassa.

Ethics declarations

Funding

This work was supported by the Italian Association for Cancer Research (AIRC), Milan, Italy (MFAG14456 to Laura Carrassa), and partially supported by the Gelu Foundation (to Francesco Bertoni).

Conflict of Interest

The authors declare no competing financial interests.

Electronic supplementary material

ESM 1

(PDF 718 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Restelli, V., Lupi, M., Vagni, M. et al. Combining Ibrutinib with Chk1 Inhibitors Synergistically Targets Mantle Cell Lymphoma Cell Lines. Targ Oncol 13, 235–245 (2018). https://doi.org/10.1007/s11523-018-0553-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11523-018-0553-6

Search

Navigation