Skip to main content

Advertisement

SpringerLink
Log in

Transcriptomic rationale for the synergy observed with dasatinib + bortezomib + dexamethasone in multiple myeloma

  • Original Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Abstract

Despite the advantage observed with novel drugs such as bortezomib, thalidomide, or lenalidomide, multiple myeloma (MM) remains incurable and there is a clear need for new drugs or combinations based on the pathogenetic mechanism of MM. One of the proposed mechanisms in MM pathogenesis is the involvement of kinase molecules in the growth and survival of myelomatous cells. In this study, we have explored the optimal combination for dasatinib, a tyrosine kinase inhibitor, in MM cells. A clear synergistic effect was observed with the triple combination of dasatinib with bortezomib and dexamethasone which was evident even in the presence of bone marrow microenvironment. Experiments performed on freshly isolated patients’ cells also demonstrated potentiation of response in the triple as compared with the agents alone or in double combinations. Gene expression profiling experiments provided some clues on the transcriptional rationale underlying this potentiation, as the triple combination led to significant deregulation of genes involved in cell death, cell growth, proliferation, DNA replication, repair and recombination, and cell–cell signaling. Some of these results were further confirmed by apoptosis and cell cycle experiments and also by Western blot and PCR. These data provide the rationale for the use of this novel combination in MM 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

Similar content being viewed by others

References

  1. Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, Zeldenrust SR, Dingli D, Russell SJ, Lust JA, Greipp PR, Kyle RA, Gertz MA (2008) Improved survival in multiple myeloma and the impact of novel therapies. Blood 111(5):2516–2520

    Article  PubMed  CAS  Google Scholar 

  2. Merchionne F, Perosa F, Dammacco F (2007) New therapies in multiple myeloma. Clin Exp Med 7(3):83–97

    Article  PubMed  CAS  Google Scholar 

  3. Ocio EM, Mateos MV, Maiso P, Pandiella A, San-Miguel JF (2008) New drugs in multiple myeloma: mechanisms of action and phase I/II clinical findings. Lancet Oncol 9(12):1157–1165

    Article  PubMed  CAS  Google Scholar 

  4. Coluccia AM, Cirulli T, Neri P, Mangieri D, Colanardi MC, Gnoni A, Di Renzo N, Dammacco F, Tassone P, Ribatti D, Gambacorti-Passerini C, Vacca A (2008) Validation of PDGFRbeta and c-Src tyrosine kinases as tumor/vessel targets in patients with multiple myeloma: preclinical efficacy of the novel, orally available inhibitor dasatinib. Blood 112(4):1346–1356

    Article  PubMed  CAS  Google Scholar 

  5. Carvajal-Vergara X, Tabera S, Montero JC, Esparis-Ogando A, Lopez-Perez R, Mateo G, Gutierrez N, Parmo-Cabanas M, Teixido J, San Miguel JF, Pandiella A (2005) Multifunctional role of Erk5 in multiple myeloma. Blood 105(11):4492–4499

    Article  PubMed  CAS  Google Scholar 

  6. Younes H, Leleu X, Hatjiharissi E, Moreau AS, Hideshima T, Richardson P, Anderson KC, Ghobrial IM (2007) Targeting the phosphatidylinositol 3-kinase pathway in multiple myeloma. Clin Cancer Res 13(13):3771–3775

    Article  PubMed  CAS  Google Scholar 

  7. Montero JC, Lopez-Perez R, San Miguel JF, Pandiella A (2008) Expression of c-Kit isoforms in multiple myeloma: differences in signaling and drug sensitivity. Haematologica 93(6):851–859

    Article  PubMed  CAS  Google Scholar 

  8. Tai YT, Fulciniti M, Hideshima T, Song W, Leiba M, Li XF, Rumizen M, Burger P, Morrison A, Podar K, Chauhan D, Tassone P, Richardson P, Munshi NC, Ghobrial IM, Anderson KC (2007) Targeting MEK induces myeloma-cell cytotoxicity and inhibits osteoclastogenesis. Blood 110(5):1656–1663

    Article  PubMed  CAS  Google Scholar 

  9. Mateo G, Montalban MA, Vidriales MB, Lahuerta JJ, Mateos MV, Gutierrez N, Rosinol L, Montejano L, Blade J, Martinez R, de la Rubia J, Diaz-Mediavilla J, Sureda A, Ribera JM, Ojanguren JM, de Arriba F, Palomera L, Terol MJ, Orfao A, San Miguel JF (2008) Prognostic value of immunophenotyping in multiple myeloma: a study by the PETHEMA/GEM cooperative study groups on patients uniformly treated with high-dose therapy. J Clin Oncol 26(16):2737–2744

    Article  PubMed  Google Scholar 

  10. Pandiella A, Carvajal-Vergara X, Tabera S, Mateo G, Gutierrez N, San Miguel JF (2003) Imatinib mesylate (STI571) inhibits multiple myeloma cell proliferation and potentiates the effect of common antimyeloma agents. Br J Haematol 123(5):858–868

    Article  PubMed  CAS  Google Scholar 

  11. Dispenzieri A, Gertz MA, Lacy MQ, Geyer SM, Greipp PR, Rajkumar SV, Kimlinger T, Lust JA, Fonseca R, Allred J, Witzig TE (2006) A phase II trial of imatinib in patients with refractory/relapsed myeloma. Leuk Lymphoma 47(1):39–42

    Article  PubMed  CAS  Google Scholar 

  12. Lombardo LJ, Lee FY, Chen P, Norris D, Barrish JC, Behnia K, Castaneda S, Cornelius LA, Das J, Doweyko AM, Fairchild C, Hunt JT, Inigo I, Johnston K, Kamath A, Kan D, Klei H, Marathe P, Pang S, Peterson R, Pitt S, Schieven GL, Schmidt RJ, Tokarski J, Wen ML, Wityak J, Borzilleri RM (2004) Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem 47(27):6658–6661

    Article  PubMed  CAS  Google Scholar 

  13. Schittenhelm MM, Shiraga S, Schroeder A, Corbin AS, Griffith D, Lee FY, Bokemeyer C, Deininger MW, Druker BJ, Heinrich MC (2006) Dasatinib (BMS-354825), a dual SRC/ABL kinase inhibitor, inhibits the kinase activity of wild-type, juxtamembrane, and activation loop mutant KIT isoforms associated with human malignancies. Cancer Res 66(1):473–481

    Article  PubMed  CAS  Google Scholar 

  14. Steinberg M (2007) Dasatinib: a tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia and philadelphia chromosome-positive acute lymphoblastic leukemia. Clin Ther 29(11):2289–2308

    Article  PubMed  CAS  Google Scholar 

  15. Richardson PG, Chanan-Khan AA, Lonial S, Krishnan AY, Carroll MP, Alsina M, Albitar M, Berman D, Messina M, Anderson KC (2011) Tanespimycin and bortezomib combination treatment in patients with relapsed or relapsed and refractory multiple myeloma: results of a phase 1/2 study. Br J Haematol 153(6):729–740

    Article  PubMed  CAS  Google Scholar 

  16. Richardson P, Lonial S, Jakubowiak A, Krishnan A, Wolf J, Densmore J (2007) Multi-center phase II study of perifosine (KRX-0401) alone and in combination with dexamethasone (dex) for patients with relapsed or relapsed/refractory multiple myeloma (MM): Promising activity as combination therapy with manageable toxicity. Blood 110(11):353a-Abstract 1164

    Google Scholar 

  17. Richardson P, Mitsiades C, Colson K, Reilly E, McBride L, Chiao J, Sun L, Ricker J, Rizvi S, Oerth C, Atkins B, Fearen I, Anderson K, Siegel D (2008) Phase I trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) in patients with advanced multiple myeloma. Leuk Lymphoma 49(3):502–507

    Article  PubMed  CAS  Google Scholar 

  18. Wolf JL, Siegel D, Matous J, Lonial S, Goldschmidt H, Schmitt S (2008) A phase II study of oral panobinostat (LBH589) in adult patients with advanced refractory multiple myeloma. ASH Annual Meet Abstr 112(11):2774

    Google Scholar 

  19. McMillin DW, Delmore J, Weisberg E, Negri JM, Geer DC, Klippel S, Mitsiades N, Schlossman RL, Munshi NC, Kung AL, Griffin JD, Richardson PG, Anderson KC, Mitsiades CS (2010) Tumor cell-specific bioluminescence platform to identify stroma-induced changes to anticancer drug activity. Nat Med 16(4):483–489

    Article  PubMed  CAS  Google Scholar 

  20. Mihara K, Imai C, Coustan-Smith E, Dome JS, Dominici M, Vanin E, Campana D (2003) Development and functional characterization of human bone marrow mesenchymal cells immortalized by enforced expression of telomerase. Br J Haematol 120(5):846–849

    Article  PubMed  CAS  Google Scholar 

  21. Maiso P, Carvajal-Vergara X, Ocio EM, Lopez-Perez R, Mateo G, Gutierrez N, Atadja P, Pandiella A, San Miguel JF (2006) The histone deacetylase inhibitor LBH589 is a potent antimyeloma agent that overcomes drug resistance. Cancer Res 66(11):5781–5789

    Article  PubMed  CAS  Google Scholar 

  22. 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  PubMed  CAS  Google Scholar 

  23. Chauhan D, Pandey P, Hideshima T, Treon S, Raje N, Davies FE, Shima Y, Tai YT, Rosen S, Avraham S, Kharbanda S, Anderson KC (2000) SHP2 mediates the protective effect of interleukin-6 against dexamethasone-induced apoptosis in multiple myeloma cells. J Biol Chem 275(36):27845–27850

    PubMed  CAS  Google Scholar 

  24. Cheung WC, Van Ness B (2001) The bone marrow stromal microenvironment influences myeloma therapeutic response in vitro. Leukemia 15(2):264–271

    Article  PubMed  CAS  Google Scholar 

  25. Honemann D, Chatterjee M, Savino R, Bommert K, Burger R, Gramatzki M, Dorken B, Bargou RC (2001) The IL-6 receptor antagonist SANT-7 overcomes bone marrow stromal cell-mediated drug resistance of multiple myeloma cells. Int J Cancer 93(5):674–680

    Article  PubMed  CAS  Google Scholar 

  26. Marcu KB, Bossone SA, Patel AJ (1992) myc function and regulation. Annu Rev Biochem 61:809–860

    Article  PubMed  CAS  Google Scholar 

  27. Podar K, Anderson KC (2010) A therapeutic role for targeting c-Myc/Hif-1-dependent signaling pathways. Cell Cycle (Georgetown, Tex) 9(9):1722–1728

    Article  CAS  Google Scholar 

  28. Shi Y, Frost PJ, Hoang BQ, Benavides A, Sharma S, Gera JF, Lichtenstein AK (2008) IL-6-induced stimulation of c-Myc translation in multiple myeloma cells is mediated by myc internal ribosome entry site function and the RNA-binding protein, hnRNP A1. Cancer Res 68(24):10215–10222

    Article  PubMed  CAS  Google Scholar 

  29. Cobbold LC, Wilson LA, Sawicka K, King HA, Kondrashov AV, Spriggs KA, Bushell M, Willis AE (2010) Upregulated c-Myc expression in multiple myeloma by internal ribosome entry results from increased interactions with and expression of PTB-1 and YB-1. Oncogene 29(19):2884–2891

    Article  PubMed  CAS  Google Scholar 

  30. Schewe DM, Aguirre-Ghiso JA (2009) Inhibition of eIF2alpha dephosphorylation maximizes bortezomib efficiency and eliminates quiescent multiple myeloma cells surviving proteasome inhibitor therapy. Cancer Res 69(4):1545–1552

    Article  PubMed  CAS  Google Scholar 

  31. Lentzsch S, Gries M, Janz M, Bargou R, Dorken B, Mapara MY (2003) Macrophage inflammatory protein 1-alpha (MIP-1 alpha) triggers migration and signaling cascades mediating survival and proliferation in multiple myeloma (MM) cells. Blood 101(9):3568–3573

    Article  PubMed  CAS  Google Scholar 

  32. Han JH, Choi SJ, Kurihara N, Koide M, Oba Y, Roodman GD (2001) Macrophage inflammatory protein-1alpha is an osteoclastogenic factor in myeloma that is independent of receptor activator of nuclear factor kappaB ligand. Blood 97(11):3349–3353

    Article  PubMed  CAS  Google Scholar 

  33. Vallet S, Pozzi S, Patel K, Vaghela N, Fulciniti MT, Veiby P, Hideshima T, Santo L, Cirstea D, Scadden DT, Anderson KC, Raje N (2011) A novel role for CCL3 (MIP-1alpha) in myeloma-induced bone disease via osteocalcin downregulation and inhibition of osteoblast function. Leukemia. doi:10.1038/leu.2011.43

  34. Cao Y, Luetkens T, Kobold S, Hildebrandt Y, Gordic M, Lajmi N, Meyer S, Bartels K, Zander AR, Bokemeyer C, Kroger N, Atanackovic D (2010) The cytokine/chemokine pattern in the bone marrow environment of multiple myeloma patients. Exp Hematol 38(10):860–867

    Article  PubMed  CAS  Google Scholar 

  35. Moller C, Stromberg T, Juremalm M, Nilsson K, Nilsson G (2003) Expression and function of chemokine receptors in human multiple myeloma. Leukemia 17(1):203–210

    Article  PubMed  CAS  Google Scholar 

  36. Vallet S, Raje N, Ishitsuka K, Hideshima T, Podar K, Chhetri S, Pozzi S, Breitkreutz I, Kiziltepe T, Yasui H, Ocio EM, Shiraishi N, Jin J, Okawa Y, Ikeda H, Mukherjee S, Vaghela N, Cirstea D, Ladetto M, Boccadoro M, Anderson KC (2007) MLN3897, a novel CCR1 inhibitor, impairs osteoclastogenesis and inhibits the interaction of multiple myeloma cells and osteoclasts. Blood 110(10):3744–3752

    Article  PubMed  CAS  Google Scholar 

  37. Vallet S, Anderson KC (2011) CCR1 as a target for multiple myeloma. Expert Opin Ther Targets. doi:10.1517/14728222.2011.586634

Download references

Aknowledgements

The authors thank Montserrat Martín and Lorena González (CIC-IBMCC, Universidad de Salamanca-CSIC, Salamanca, Spain) for their excellent technical work and assistance. We also thank Isabel Isidro, Teresa Prieto and Almudena Martín (Hospital Universitario de Salamanca, Salamanca, Spain) for their help with myeloma patient samples.

Funding

This work was supported by grants from the Ministerio de Ciencia e Innovación - ISCIII (PI081825); Fundación de Investigación Médica Mutua Madrileña (AP27262008); Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León; the Spanish Myeloma Network Program (RD06/0020/0006), and Grupos de Excelencia de Castilla y León (Ref. GR33). The CIC receives support from the European Community through the regional development funding program (FEDER). AG-G was supported by the “Proyecto Centro en Red de Medicina Regenerativa y Terapia Celular de Castilla y León (Consejería de Sanidad JCyL–ISCIII)”.

Disclosures

FL is an employee of Bristol-Myers Squibb.

Author information

Authors and Affiliations

  1. Centro de Investigación del Cáncer, IBMCC (CSIC-Universidad de Salamanca), Salamanca, Spain

    Edvan de Queiroz Crusoe, Patricia Maiso, Diego Fernandez-Lazaro, Laura San-Segundo, Mercedes Garayoa, Antonio Garcia-Gomez, Norma C. Gutierrez, Manuel Delgado, Enrique Colado, Jesus Martin-Sanchez & Enrique M. Ocio

  2. Hospital Universitario de Salamanca, Salamanca, Spain

    Edvan de Queiroz Crusoe, Norma C. Gutierrez, Enrique Colado, Jesus Martin-Sanchez & Enrique M. Ocio

  3. Santa Casa de Sao Paulo School of Medicine, São Paulo, Brasil

    Edvan de Queiroz Crusoe

  4. Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ, USA

    Francis Y. Lee

  5. Department of Hematology, University Hospital of Salamanca, P. San Vicente, 58–182, 37007, Salamanca, Spain

    Enrique M. Ocio

Authors
  1. Edvan de Queiroz Crusoe
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Patricia Maiso
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Diego Fernandez-Lazaro
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Laura San-Segundo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mercedes Garayoa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Antonio Garcia-Gomez
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Norma C. Gutierrez
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Manuel Delgado
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Enrique Colado
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jesus Martin-Sanchez
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Francis Y. Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Enrique M. Ocio
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Enrique M. Ocio.

Rights and permissions

Reprints and permissions

About this article

Cite this article

de Queiroz Crusoe, E., Maiso, P., Fernandez-Lazaro, D. et al. Transcriptomic rationale for the synergy observed with dasatinib + bortezomib + dexamethasone in multiple myeloma. Ann Hematol 91, 257–269 (2012). https://doi.org/10.1007/s00277-011-1287-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-011-1287-z

Keywords

Search

Navigation