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.

  • Letter to the Editor
  • Published:

Anti-tumor activities of selective HSP90α/β inhibitor, TAS-116, in combination with bortezomib in multiple myeloma

Leukemia volume 29, pages 510–514 (2015)Cite this article

Subjects

Heat shock protein 90 (HSP90) is a highly conserved molecular chaperone that interacts with various client proteins in eukaryotic cells:1 Akt (PI3K/Akt pathway), interleukin-6 R (JAK/STAT pathway), Bcr-Abl (RAS/ERK pathway), Cyclin-dependent kinase 4, 6, 9 (cell cycling) and IκB kinases (NF-κB pathway).2 The expression of HSP90 is upregulated (2- to 10-fold) in tumor cells compared with normal cells, reflecting multiple oncogenic pathways and maintenance of homeostasis within tumor cells.1, 2 Because HSP90 inhibition triggers downregulation /degradation of client proteins and triggers apoptosis, it is considered a promising target for novel targeted therapies. Indeed HSP90 inhibitors (for example, geldanamycin analog 17-allylamino-17-demethoxy-geldanamycin (17-AAG), resorcinol derivatives, purine analogs) have shown early promising results in vitro and in vivo in solid tumors and some hematological malignancies, including multiple myeloma (MM).3, 4 However, some clinical studies have been discontinued due to adverse effects, including ocular toxicity.3, 5 Therefore, development of a next-generation less-toxic HSP90 inhibitor remains an important therapeutic goal.

In the present study, we demonstrate in vitro and in vivo preclinical anti-MM activity of TAS-116, an oral selective HSP90α/β inhibitor, alone and in combination with bortezomib (BTZ). TAS-116 shows favorable oral bioavailability in rodent and non-rodent species, as well as good metabolic stability.6 Importantly, TAS-116 demonstrates less ocular toxicity and greater anti-tumor activity in multiple xenograft models, compared with other HSP90 inhibitors at their maximal tolerated dose (MTD) in rats.6, 7 Our data therefore provide the preclinical framework for clinical evaluation of TAS-116, alone and with BTZ, to improve patient outcome in MM.

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

References

  1. Isaacs JS, Xu W, Neckers L . Heat shock protein 90 as a molecular target for cancer therapeutics. Cancer Cell 2003; 3: 213–217.

    Article  CAS  PubMed  Google Scholar 

  2. Khong T, Spencer A . Targeting HSP 90 induces apoptosis and inhibits critical survival and proliferation pathways in multiple myeloma. Mol Cancer Ther 2011; 10: 1909–1917.

    Article  CAS  PubMed  Google Scholar 

  3. Garcia-Carbonero R, Carnero A, Paz-Ares L . Inhibition of HSP90 molecular chaperones: moving into the clinic. Lancet Oncol 2013; 14: e358–e369.

    Article  CAS  PubMed  Google Scholar 

  4. Mitsiades CS, Mitsiades NS, McMullan CJ, Poulaki V, Kung AL, Davies FE et al. Antimyeloma activity of heat shock protein-90 inhibition. Blood 2006; 107: 1092–1100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Rajan A, Kelly RJ, Trepel JB, Kim YS, Alarcon SV, Kummar S et al. A phase I study of PF-04929113 (SNX-5422), an orally bioavailable heat shock protein 90 inhibitor, in patients with refractory solid tumor malignancies and lymphomas. Clin Cancer Res 2011; 17: 6831–6839.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ohkubo S, Muraoka H, Hashimoto A, Ito S, Ito K, Shibata Y et al. TAS-116, a novel, orally bioavailable hsp90α/β selective inhibitor demonstrates highly potent antitumor activity in preclinical models with a favorable pk profile. Eur J Cancer 2012; 48: 89 (abstract 291).

    Article  Google Scholar 

  7. Kodama Y, Hitotsumachi H, Shibata Y, Suzuki T, Sakuragi M, Kitade M et al. TAS-116, a novel, orally bioavailable highly potent hsp90α/β selective inhibitor demonstrates favorable tissue distribution properties which lead to minimized ocular toxicity. Eur J Cancer 2012; 48: 89 (abstract 290).

    Article  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  9. Chauhan D, Li G, Shringarpure R, Podar K, Ohtake Y, Hideshima T et al. Blockade of Hsp27 overcomes Bortezomib/proteasome inhibitor PS-341 resistance in lymphoma cells. Cancer Res 2003; 63: 6174–6177.

    CAS  PubMed  Google Scholar 

  10. Zhang L, Fok JH, Davies FE . Heat shock proteins in multiple myeloma. Oncotarget 2014; 5: 1132–1148.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Hideshima T, Chauhan D, Kiziltepe T, Ikeda H, Okawa Y, Podar K et al. Biologic sequelae of I{kappa}B kinase (IKK) inhibition in multiple myeloma: therapeutic implications. Blood 2009; 113: 5228–5236.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Davenport EL, Zeisig A, Aronson LI, Moore HE, Hockley S, Gonzalez D et al. Targeting heat shock protein 72 enhances Hsp90 inhibitor-induced apoptosis in myeloma. Leukemia 2010; 24: 1804–1807.

    Article  CAS  PubMed  Google Scholar 

  13. Obeng EA, Carlson LM, Gutman DM, Harrington WJ Jr, Lee KP, Boise LH . Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood 2006; 107: 4907–4916.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hideshima T, Ikeda H, Chauhan D, Okawa Y, Raje N, Podar K et al. Bortezomib induces canonical nuclear factor-kappaB activation in multiple myeloma cells. Blood 2009; 114: 1046–1052.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wu WC, Wu MH, Chang YC, Hsieh MC, Wu HJ, Cheng KC et al. Geldanamycin and its analog induce cytotoxicity in cultured human retinal pigment epithelial cells. Exp Eye Res 2010; 91: 211–219.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by the National Institute of Health Grants (SPORE-P50100707, P01-CA078378, P01-155258 (KCA, NCM), R01-CA050947 (KCA), and R01-178264 (TH, KCA); and SENSHIN Medical Research Foundation (RS). KCA is an American Cancer Society Clinical Research Professor.

Author information

Authors and Affiliations

  1. Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA, USA

    R Suzuki, T Hideshima, N Mimura, J Minami, H Ohguchi, S Kikuchi, Y Yoshida, G Gorgun, D Cirstea, F Cottini, J Jakubikova, Y-T Tai, D Chauhan, P G Richardson & K C Anderson

  2. Tsukuba Research Center, TAIHO PHARMACEUTICAL CO. LTD., Tsukuba, Japan

    T Utsugi

  3. VA Boston Healthcare System, Jerome Lipper Multiple Myeloma Center, Harvard Medical School, Dana-Farber Cancer Institute,, Boston, MA, USA

    N C Munshi

Authors
  1. R Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T Hideshima
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N Mimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J Minami
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. H Ohguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S Kikuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Y Yoshida
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. G Gorgun
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. D Cirstea
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. F Cottini
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. J Jakubikova
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Y-T Tai
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. D Chauhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. P G Richardson
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. N C Munshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. T Utsugi
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. K C Anderson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to K C Anderson.

Ethics declarations

Competing interests

TU is an employee at Taiho Pharmaceutical Co., Ltd. Y-TT is a consultant for Onyx. DC is a consultant for Oncopeptides AB. PGR is a member of advisory board for Celgene, Millennium, Johnson and Johnson, Novartis and Bristol–Myers Squibb. NM is a member of advisory board for Millennium, Celgene and Novartis. TH is a consultant for Acetylon Pharmaceuticals. KCA is a member of advisory board for Onyx, Celgene, Gilead and Sanofi-Aventis, and is a scientific founder of Acetylon and Oncopep. Other authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Suzuki, R., Hideshima, T., Mimura, N. et al. Anti-tumor activities of selective HSP90α/β inhibitor, TAS-116, in combination with bortezomib in multiple myeloma. Leukemia 29, 510–514 (2015). https://doi.org/10.1038/leu.2014.300

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2014.300

This article is cited by

Search

Advanced search

Quick links