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Targeted Oncology

, Volume 13, Issue 2, pp 235–245 | Cite as

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

  • Valentina Restelli
  • Monica Lupi
  • Micaela Vagni
  • Rosaria Chilà
  • Francesco Bertoni
  • Giovanna Damia
  • Laura Carrassa
Original Research Article

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.

Notes

Acknowledgments

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

Compliance with Ethical Standards

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.

Supplementary material

11523_2018_553_MOESM1_ESM.pdf (719 kb)
ESM 1 (PDF 718 kb)

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Valentina Restelli
    • 1
  • Monica Lupi
    • 1
  • Micaela Vagni
    • 1
  • Rosaria Chilà
    • 1
  • Francesco Bertoni
    • 2
    • 3
  • Giovanna Damia
    • 1
  • Laura Carrassa
    • 1
  1. 1.Laboratory of Molecular Pharmacology and Laboratory of Cancer Pharmacology, Department of OncologyIRCCS-Istituto di Ricerche Farmacologiche “Mario Negri” (IRFMN)MilanItaly
  2. 2.Institute of Oncology Research (IOR)Università della Svizzera Italiana (USI)BellinzonaSwitzerland
  3. 3.Oncology Institute of Southern Switzerland (IOSI)BellinzonaSwitzerland

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