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Ibrutinib (ImbruvicaTM) potently inhibits ErbB receptor phosphorylation and cell viability of ErbB2-positive breast cancer cells

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Summary

Ibrutinib (formerly PCI-32765) is a specific, irreversible, and potent inhibitor of Burton’s tyrosine kinase (BTK) developed for the treatment of several forms of blood cancer. It is now an FDA-approved drug marketed under the name ImbruvicaTM (Pharmacyclics, Inc.) and successfully used as an orally administered second-line drug in the treatment of mantle cell lymphoma. Since BTK is predominantly expressed in hematopoietic cells, the sensitivity of solid tumor cells to Ibrutinib has not been analyzed. In this study, we determined the effect of Ibrutinib on breast cancer cells. We demonstrate that Ibrutinib efficiently reduces the phosphorylation of the receptor tyrosine kinases ErbB1, ErbB2 and ErbB3, thereby suppressing AKT and MAPK signaling in ErbB2-positive (ErbB2+) breast cancer cell lines. Treatment with Ibrutinib significantly reduced the viability of ErbB2+ cell lines with IC50 values at nanomolar concentrations, suggesting therapeutic potential of Ibrutinib in breast cancer. Combined treatment with Ibrutinib and the dual PI3K/mTOR inhibitor BEZ235 synergistically reduces cell viability of ErbB2+ breast cancer cells. Combination indices below 0.25 at 50 % inhibition of cell viability were determined by the Chou-Talalay method. Therefore, the combination of Ibrutinib and canonical PI3K pathway inhibitors could be a new and effective approach in the treatment of breast cancer with activated ErbB receptors. Ibrutinib could thus become a valuable component of targeted therapy in aggressive ErbB2+ breast cancer.

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References

  1. Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JW, Comber H, Forman D, Bray F (2013) Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer 49(6):1374–1403. doi:10.1016/j.ejca.2012.12.027

    Article  CAS  PubMed  Google Scholar 

  2. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235(4785):177–182

    Article  CAS  PubMed  Google Scholar 

  3. Witton CJ, Reeves JR, Going JJ, Cooke TG, Bartlett JM (2003) Expression of the HER1-4 family of receptor tyrosine kinases in breast cancer. J Pathol 200(3):290–297. doi:10.1002/path.1370

    Article  CAS  PubMed  Google Scholar 

  4. Arteaga CL, Engelman JA (2014) ERBB receptors: from oncogene discovery to basic science to mechanism-based cancer therapeutics. Cancer Cell 25(3):282–303. doi:10.1016/j.ccr.2014.02.025

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Coussens L, Yang-Feng TL, Liao YC, Chen E, Gray A, McGrath J, Seeburg PH, Libermann TA, Schlessinger J, Francke U et al (1985) Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science 230(4730):1132–1139

    Article  CAS  PubMed  Google Scholar 

  6. Arpino G, Wiechmann L, Osborne CK, Schiff R (2008) Crosstalk between the estrogen receptor and the HER tyrosine kinase receptor family: molecular mechanism and clinical implications for endocrine therapy resistance. Endocr Rev 29(2):217–233. doi:10.1210/er.2006-0045

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Modjtahedi H, Cho BC, Michel MC, Solca F (2014) A comprehensive review of the preclinical efficacy profile of the ErbB family blocker afatinib in cancer. Naunyn Schmiedeberg’s Arch Pharmacol. doi:10.1007/s00210-014-0967-3

    Google Scholar 

  8. Rexer BN, Arteaga CL (2012) Intrinsic and acquired resistance to HER2-targeted therapies in HER2 gene-amplified breast cancer: mechanisms and clinical implications. Crit Rev Oncog 17(1):1–16

    Article  PubMed Central  PubMed  Google Scholar 

  9. Zhou W, Ercan D, Chen L, Yun CH, Li D, Capelletti M, Cortot AB, Chirieac L, Iacob RE, Padera R, Engen JR, Wong KK, Eck MJ, Gray NS, Janne PA (2009) Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Nature 462(7276):1070–1074. doi:10.1038/nature08622

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Tibes R, Trent J, Kurzrock R (2005) Tyrosine kinase inhibitors and the dawn of molecular cancer therapeutics. Annu Rev Pharmacol Toxicol 45:357–384. doi:10.1146/annurev.pharmtox.45.120403.100124

    Article  CAS  PubMed  Google Scholar 

  11. Walter AO, Sjin RT, Haringsma HJ, Ohashi K, Sun J, Lee K, Dubrovskiy A, Labenski M, Zhu Z, Wang Z, Sheets M, St Martin T, Karp R, van Kalken D, Chaturvedi P, Niu D, Nacht M, Petter RC, Westlin W, Lin K, Jaw-Tsai S, Raponi M, Van Dyke T, Etter J, Weaver Z, Pao W, Singh J, Simmons AD, Harding TC, Allen A (2013) Discovery of a mutant-selective covalent inhibitor of EGFR that overcomes T790M-mediated resistance in NSCLC. Cancer Discov 3(12):1404–1415. doi:10.1158/2159-8290.CD-13-0314

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Garske AL, Peters U, Cortesi AT, Perez JL, Shokat KM (2011) Chemical genetic strategy for targeting protein kinases based on covalent complementarity. Proc Natl Acad Sci U S A 108(37):15046–15052. doi:10.1073/pnas.1111239108

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Blair JA, Rauh D, Kung C, Yun CH, Fan QW, Rode H, Zhang C, Eck MJ, Weiss WA, Shokat KM (2007) Structure-guided development of affinity probes for tyrosine kinases using chemical genetics. Nat Chem Biol 3(4):229–238. doi:10.1038/nchembio866

    Article  CAS  PubMed  Google Scholar 

  14. Cohen MS, Zhang C, Shokat KM, Taunton J (2005) Structural bioinformatics-based design of selective, irreversible kinase inhibitors. Science 308(5726):1318–1321. doi:10.1126/science1108367

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Zhang J, Yang PL, Gray NS (2009) Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer 9(1):28–39. doi:10.1038/nrc2559

    Article  PubMed  Google Scholar 

  16. Lopez-Herrera G, Vargas-Hernandez A, Gonzalez-Serrano ME, Berron-Ruiz L, Rodriguez-Alba JC, Espinosa-Rosales F, Santos-Argumedo L (2014) Bruton’s tyrosine kinase—an integral protein of B cell development that also has an essential role in the innate immune system. J Leukoc Biol 95(2):243–250. doi:10.1189/jlb.0513307

    Article  PubMed  Google Scholar 

  17. Hendriks RW, Yuvaraj S, Kil LP (2014) Targeting Bruton’s tyrosine kinase in B cell malignancies. Nat Rev Cancer 14(4):219–232. doi:10.1038/nrc3702

    Article  CAS  PubMed  Google Scholar 

  18. Buggy JJ, Elias L (2012) Bruton tyrosine kinase (BTK) and its role in B-cell malignancy. Int Rev Immunol 31(2):119–132. doi:10.3109/08830185.2012.664797

    Article  CAS  PubMed  Google Scholar 

  19. Leproult E, Barluenga S, Moras D, Wurtz JM, Winssinger N (2011) Cysteine mapping in conformationally distinct kinase nucleotide binding sites: application to the design of selective covalent inhibitors. J Med Chem 54(5):1347–1355. doi:10.1021/jm101396q

    Article  CAS  PubMed  Google Scholar 

  20. Brown JR (2013) Ibrutinib (PCI-32765), the first BTK (Bruton’s tyrosine kinase) inhibitor in clinical trials. Curr Hematol Malignancy Rep 8(1):1–6. doi:10.1007/s11899-012-0147-9

    Article  Google Scholar 

  21. Dias AL, Jain D (2014) Ibrutinib: a New frontier in the treatment of chronic lymphocytic leukemia by Bruton’s tyrosine kinase inhibition. Cardiovasc Hematol Agents Med Chem 11(4):265–271

    Article  Google Scholar 

  22. Grabinski N, Mollmann K, Milde-Langosch K, Muller V, Schumacher U, Brandt B, Pantel K, Jucker M (2014) AKT3 regulates ErbB2, ErbB3 and estrogen receptor alpha expression and contributes to endocrine therapy resistance of ErbB2(+) breast tumor cells from Balb-neuT mice. Cell Signal 26(5):1021–1029. doi:10.1016/j.cellsig.2014.01.018

    Article  CAS  PubMed  Google Scholar 

  23. Chou TC, Talalay P (1984) Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 22:27–55

    Article  CAS  PubMed  Google Scholar 

  24. Grabinski N, Ewald F, Hofmann BT, Staufer K, Schumacher U, Nashan B, Jucker M (2012) Combined targeting of AKT and mTOR synergistically inhibits proliferation of hepatocellular carcinoma cells. Mol Cancer 11:85. doi:10.1186/1476-4598-11-85

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Holbro T, Beerli RR, Maurer F, Koziczak M, Barbas CF 3rd, Hynes NE (2003) The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation. Proc Natl Acad Sci U S A 100(15):8933–8938. doi:10.1073/pnas.1537685100

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Wu H, Wang W, Liu F, Weisberg EL, Tian B, Chen Y, Li B, Wang A, Wang B, Zhao Z, McMillin DW, Hu C, Li H, Wang J, Liang Y, Buhrlage SJ, Liang J, Liu J, Yang G, Brown JR, Treon SP, Mitsiades CS, Griffin JD, Liu Q, Gray NS (2014) Discovery of a potent covalent BTK inhibitor for B-cell lymphoma. ACS Chem Biol. doi:10.1021/cb4008524

    Google Scholar 

  27. Jiang X, Borgesi RA, McKnight NC, Kaur R, Carpenter CL, Balk SP (2007) Activation of nonreceptor tyrosine kinase Bmx/Etk mediated by phosphoinositide 3-kinase, epidermal growth factor receptor, and ErbB3 in prostate cancer cells. J Biol Chem 282(45):32689–32698. doi:10.1074/jbc.M703412200

    Article  CAS  PubMed  Google Scholar 

  28. Chen S, Jiang X, Gewinner CA, Asara JM, Simon NI, Cai C, Cantley LC, Balk SP (2013) Tyrosine kinase BMX phosphorylates phosphotyrosine-primed motif mediating the activation of multiple receptor tyrosine kinases. Sci Signal 6(277):ra40. doi:10.1126/scisignal.2003936

    Article  PubMed Central  PubMed  Google Scholar 

  29. Carmi C, Mor M, Petronini PG, Alfieri RR (2012) Clinical perspectives for irreversible tyrosine kinase inhibitors in cancer. Biochem Pharmacol 84(11):1388–1399. doi:10.1016/j.bcp.2012.07.031

    Article  CAS  PubMed  Google Scholar 

  30. Hur W, Velentza A, Kim S, Flatauer L, Jiang X, Valente D, Mason DE, Suzuki M, Larson B, Zhang J, Zagorska A, Didonato M, Nagle A, Warmuth M, Balk SP, Peters EC, Gray NS (2008) Clinical stage EGFR inhibitors irreversibly alkylate Bmx kinase. Bioorg Med Chem Lett 18(22):5916–5919. doi:10.1016/j.bmcl.2008.07.062

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Mathews Griner LA, Guha R, Shinn P, Young RM, Keller JM, Liu D, Goldlust IS, Yasgar A, McKnight C, Boxer MB, Duveau DY, Jiang JK, Michael S, Mierzwa T, Huang W, Walsh MJ, Mott BT, Patel P, Leister W, Maloney DJ, Leclair CA, Rai G, Jadhav A, Peyser BD, Austin CP, Martin SE, Simeonov A, Ferrer M, Staudt LM, Thomas CJ (2014) High-throughput combinatorial screening identifies drugs that cooperate with ibrutinib to kill activated B-cell-like diffuse large B-cell lymphoma cells. Proc Natl Acad Sci U S A 111(6):2349–2354. doi:10.1073/pnas.1311846111

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank Peter K. Vogt for guidance and support during these studies and for his help in the preparation of the manuscript. We thank Mailo Timm for perfect technical assistance.

Financial support

N.G. was funded by the Deutsche Krebshilfe (Dr. Mildred Scheel scholarship). This work was further supported by the National Cancer Institute under award number R01 CA078230 to Peter K. Vogt. This is manuscript 27046 of The Scripps Research Institute.

Conflict of interest

The authors disclose no potential conflicts of interest.

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Authors and Affiliations

  1. Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA

    Nicole Grabinski

  2. Department of Hepatobiliary and Transplant Surgery, University Medical Center Hamburg Eppendorf, Hamburg, Germany

    Florian Ewald

  3. Institute of Biochemistry and Signal Transduction, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany

    Nicole Grabinski

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  1. Nicole Grabinski
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Correspondence to Nicole Grabinski.

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Grabinski, N., Ewald, F. Ibrutinib (ImbruvicaTM) potently inhibits ErbB receptor phosphorylation and cell viability of ErbB2-positive breast cancer cells. Invest New Drugs 32, 1096–1104 (2014). https://doi.org/10.1007/s10637-014-0141-2

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  • DOI: https://doi.org/10.1007/s10637-014-0141-2

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