Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Sensitivity and Resistance to Therapy

Smac mimetics: implications for enhancement of targeted therapies in leukemia

Leukemia volume 24, pages 2100–2109 (2010)Cite this article

Subjects

An Erratum to this article was published on 13 July 2011

Abstract

Drug resistance is a growing concern with clinical use of tyrosine kinase inhibitors. Utilizing in vitro models of intrinsic drug resistance and stromal-mediated chemoresistance, as well as functional mouse models of progressive and residual disease, we attempted to develop a potential therapeutic approach designed to suppress leukemia recurrence following treatment with selective kinase inhibitors. The novel inhibitor of apoptosis (IAP), LCL161, was observed to potentiate the effects of tyrosine kinase inhibition against leukemic disease both in the absence and presence of a stromal protected environment. LCL161 enhanced the proapoptotic effects of nilotinib and PKC412, against leukemic disease in vitro and potentiated the activity of both kinase inhibitors against leukemic disease in vivo. In addition, LCL161 synergized in vivo with nilotinib to reduce leukemia burden significantly below the baseline level suppression exhibited by a moderate-to-high dose of nilotinib. Finally, LCL161 displayed antiproliferative effects against cells characterized by intrinsic resistance to tyrosine kinase inhibitors as a result of expression of point mutations in the protein targets of drug inhibition. These results support the idea of using IAP inhibitors in conjunction with targeted tyrosine kinase inhibition to override drug resistance and suppress or eradicate residual disease.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  1. Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 1996; 2: 561–566.

    Article  CAS  Google Scholar 

  2. Buchdunger E, Matter A, Druker BJ . Bcr-Abl inhibition as a modality of CML therapeutics. Biochim Biophys Acta 2001; 1551: M11–M18.

    CAS  Google Scholar 

  3. Deininger MW, Goldman JM, Melo JV . The molecular biology of chronic myeloid leukemia. Blood 2000; 96: 3343–3356.

    CAS  Google Scholar 

  4. Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 2001; 293: 876–880.

    Article  CAS  Google Scholar 

  5. Weisberg E, Griffin JD . Mechanism of resistance to the ABL tyrosine kinase inhibitor STI571 in BCR/ABL-transformed hematopoietic cell lines. Blood 2000; 95: 3498–3505.

    CAS  Google Scholar 

  6. Weisberg E, Manley PW, Breitenstein W, Brüggen J, Cowan-Jacob SW, Ray A et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 2005; 7: 129–141.

    Article  CAS  Google Scholar 

  7. Stirewalt DL, Radich JP . The role of FLT3 in haematopoietic malignancies. Nat Rev Cancer 2003; 3: 650–665.

    Article  CAS  Google Scholar 

  8. Weisberg E, Boulton C, Kelly LM, Manley P, Fabbro D, Meyer T et al. Inhibition of mutant FLT3 receptors in leukemia cells by the small molecule tyrosine kinase inhibitor PKC412. Cancer Cell 2002; 1: 433–443.

    Article  CAS  Google Scholar 

  9. Stone RM, De Angelo J, Galinsky I, Estey E, Klimek V, Grandin W et al. PKC412 FLT3 inhibitor therapy in AML: results of a phase II trial. Ann Hematol 2004; 83 (Suppl 1): S89–S90.

    Google Scholar 

  10. Kumagai M, Manabe A, Pui CH, Behm FG, Raimondi SC, Hancock ML et al. Stroma-supported culture in childhood B-lineage acute lymphoblastic leukemia cells predicts treatment outcome. J Clin Invest 1996; 97: 755–760.

    Article  CAS  Google Scholar 

  11. Du C, Fang M, Li Y, Li L, Wang X . Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 2000; 102: 33–42.

    Article  CAS  Google Scholar 

  12. Liu Z, Sun C, Olejniczak ET, Meadows RP, Betz SF, Oost T et al. Structural basis for binding of Smac/DIABLO to the XIAP BIR3 domain. Nature 2000; 408: 1004–1008.

    Article  CAS  Google Scholar 

  13. Wu G, Chai J, Suber TL, Wu JW, Du C, Wang X et al. Structural basis of IAP recognition by Smac/DIABLO. Nature 2000; 408: 1008–1012.

    Article  CAS  Google Scholar 

  14. Galban S, Hwang C, Rumble JM, Oetjen KA, Wright CW, Boudreault A et al. Cytoprotective effects of IAPs revealed by a small molecule antagonist. Biochem J 2009; 417: 765–771.

    Article  CAS  Google Scholar 

  15. Sensintaffar J, Scott FL, Peach R, Hager JH . XIAP is not required for human tumor cell survival in the absence of an exogenous death signal. BMC Cancer 2010; 10: 11.

    Article  Google Scholar 

  16. Weisberg E, Kung AL, Wright RD, Moreno D, Catley L, Ray A et al. Potentiation of antileukemic therapies by Smac mimetic, LBW242: effects on mutant FLT3-expressing cells. Mol Cancer Ther 2007; 6: 1951–1961.

    Article  CAS  Google Scholar 

  17. Daley GQ, Baltimore D . Transformation of an interleukin 3-dependent hematopoietic cell line by the chronic myeloid leukemia-specific p210 BCR-ABL protein. Proc Natl Acad Sci USA 1988; 85: 9312–9316.

    Article  CAS  Google Scholar 

  18. Okuda K, Golub TR, Gilliland DG, Griffin JD . p210BCR-ABL, p190BCR-ABL, and TEL/ABL activate similar signal transduction pathways in hematopoietic cell lines. Oncogene 1996; 13: 1147–1152.

    CAS  Google Scholar 

  19. Sattler M, Salgia R, Okuda K, Uemura N, Durstin MA, Pisick E et al. The proto-oncogene product p120CBL and the adaptor proteins CRKL and c-CRK link c-ABL, p190BCR-ABL and p210BCR-ABL to the phosphatidylinositol-3′ kinase pathway. Oncogene 1996; 12: 839–846.

    CAS  Google Scholar 

  20. Matulonis U, Salgia R, Okuda K, Druker B, Griffin JD . IL-3 and p210 BCR-ABL activate both unique and overlapping pathways of signal transduction in a factor-dependent myeloid cell line. Exp Hematol 1993; 21: 1460–1466.

    CAS  Google Scholar 

  21. Kelly LM, Liu Q, Kutok JL, Williams IR, Boulton CL, Gilliland DG . FLT3 internal tandem duplication mutations associated with human acute myeloid leukemias induce myeloproliferative disease in a murine bone marrow transplant model. Blood 2002; 99: 310–318.

    Article  CAS  Google Scholar 

  22. Jiang J, Paez JG, Lee JC, Bo R, Stone RM, DeAngelo DJ et al. Identifying and characterizing a novel activating mutation of the FLT3 tyrosine kinase in AML. Blood 2004; 104: 1855–1858.

    Article  CAS  Google Scholar 

  23. Cools J, Mentens N, Furet P, Fabbro D, Clark JJ, Griffin JD et al. Prediction of resistance to small molecule FLT3 inhibitors: implications for molecularly targeted therapy of acute leukemia. Cancer Res 2004; 64: 6385–6389.

    Article  CAS  Google Scholar 

  24. Armstrong SA, Kung AL, Mabon ME, Silverman LB, Stam RW, Den Boer ML et al. Validation of a therapeutic target identified by gene expression based classification. Cancer Cell 2003; 3: 173–183.

    Article  CAS  Google Scholar 

  25. Chou T-C, Talalay P . Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enz Regul 1984; 22: 27–55.

    Article  CAS  Google Scholar 

  26. Weisberg E, Wright RD, McMillin DW, Mitsiades C, Ray A, Barrett R et al. Stromal-mediated protection of tyrosine kinase inhibitor-treated BCR-ABL-expressing leukemia cells. Mol Cancer Ther 2008; 7: 1121–1129.

    Article  CAS  Google Scholar 

  27. Weisberg E, Barrett R, Liu Q, Stone R, Gray N, Griffin JD . FLT3 inhibition and mechanisms of drug resistance in mutant FLT3-positive AML. Drug Resist Updat 2009; 12: 81–89.

    Article  CAS  Google Scholar 

  28. Mony U, Jawad M, Seedhouse C, Russell N, Pallis M . Resistance to FLT3 inhibition in an in vitro model of primary AML cells with a stem cell phenotype in a defined microenvironment. Leukemia 2008; 22: 1395–1401.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

JDG is supported by NIH Grant CA66996, and a Specialized Center of Research Award from the Leukemia and Lymphoma Society. JDG is also supported by NIH Grants CA36167 and DK50654.

Author information

Author notes

  1. E Weisberg and A Ray: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Oncology/Hematologic Neoplasia, Dana Farber Cancer Institute, Boston, MA, USA

    E Weisberg, A Ray, R Barrett, E Nelson, J F Daley, S Lazo-Kallanian, R Stone, I Galinsky, D Frank & J D Griffin

  2. Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology (CBIO), Dana Farber Cancer Institute, Boston, MA, USA

    A L Christie & A L Kung

  3. Novartis Pharma AG, Basel, Switzerland

    D Porter, C Straub & L Zawel

  4. Department of Pediatric Oncology, Dana Farber Cancer Institute and Children's Hospital, Boston, MA, USA

    A L Kung

Authors
  1. E Weisberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A Ray
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R Barrett
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. E Nelson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A L Christie
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. D Porter
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. C Straub
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. L Zawel
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. J F Daley
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. S Lazo-Kallanian
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. R Stone
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. I Galinsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. D Frank
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. A L Kung
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. J D Griffin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E Weisberg.

Ethics declarations

Competing interests

JDG, RS, DF and ALK have a financial interest with Novartis Pharma AG. Employees of Novartis include DP, CS and LZ (formerly).

Additional information

Supplementary Information accompanies the paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Weisberg, E., Ray, A., Barrett, R. et al. Smac mimetics: implications for enhancement of targeted therapies in leukemia. Leukemia 24, 2100–2109 (2010). https://doi.org/10.1038/leu.2010.212

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2010.212

Keywords

This article is cited by

Search

Advanced search

Quick links