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.
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References
Vogt N, Dai B, Erdmann T, Berdel WE, Lenz G. The molecular pathogenesis of mantle cell lymphoma. Leuk Lymphoma. 2017;58(7):1530–7.
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.
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.
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.
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.
Campo E, Rule S. Mantle cell lymphoma: evolving management strategies. Blood. 2015;125(1):48–55.
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.
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.
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.
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.
Colomer D, Campo E. Unlocking new therapeutic targets and resistance mechanisms in mantle cell lymphoma. Cancer Cell. 2014;25(1):7–9.
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(9):1022–35.
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.
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.
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.
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.
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.
Ubezio P. Microcomputer experience in analysis of flow cytometric DNA distributions. Comput Programs Biomed. 1985;19(2-3):159–66.
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.
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.
Goy A. Mantle cell lymphoma: is it time for a new treatment paradigm? Hematol Oncol Clin North Am. 2016;30(6):1345–70.
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.
Tucker D, Rule S. Novel agents in mantle cell lymphoma. Expert Rev Anticancer Ther. 2017;17(6):491–506.
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.
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.
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.
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.
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.
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.
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.
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.
Acknowledgments
We thank J.D. Baggott who kindly edited the paper. This work is dedicated to the memory of Eugenio and Angela Filice.
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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).
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The authors declare no competing financial interests.
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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
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DOI: https://doi.org/10.1007/s11523-018-0553-6