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HSP-90 inhibitor ganetespib is synergistic with doxorubicin in small cell lung cancer

Oncogene volume 33, pages 4867–4876 (2014)Cite this article

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Abstract

Small cell lung cancer (SCLC) at advanced stage is considered an incurable disease. Despite good response to initial chemotherapy, the responses in SCLC patients with metastatic disease are of short duration and resistance inevitably occurs. Although several target-specific drugs have altered the paradigm of treatment for many other cancers, we have yet to witness a revolution of the same magnitude in SCLC treatment. Anthracyclines, such as doxorubicin, have definite activity in this disease, and ganetespib has shown promising activity in preclinical models but underwhelming activity as a single agent in SCLC patients. Using SCLC cell lines, we demonstrated that ganetespib (IC50: 31 nM) was much more potent than 17-allylamino-17-demethoxygeldanamycin (17-AAG), a geldanamycin derivative (IC50: 16 μM). Ganetespib inhibited SCLC cell growth via induction of persistent G2/M arrest and Caspase 3-dependent cell death. MTS assay revealed that ganetespib synergized with both doxorubicin and etoposide, two topoisomerase II inhibitors commonly used in SCLC chemotherapy. Expression of receptor-interacting serine/threonine-protein kinase 1 (RIP1), a protein that may function as a pro-survival scaffold protein or a pro-death kinase in TNFR1-activated cells, was induced by doxorubicin and downregulated by ganetespib. Depletion of RIP1 by either RIP1 small interfering RNA (siRNA) or ganetespib sensitized doxorubicin-induced cell death, suggesting that RIP1 may promote survival in doxorubicin-treated cells and that ganetespib may synergize with doxorubicin in part through the downregulation of RIP1. In comparison to ganetespib or doxorubicin alone, the ganetespib+doxorubicin combination caused significantly more growth regression and death of human SCLC xenografts in immunocompromised mice. We conclude that ganetespib and doxorubicin combination exhibits significant synergy and is efficacious in inhibiting SCLC growth in vitro and in mouse xenograft models. Our preclinical study suggests that ganetespib and doxorubicin combination therapy may be an effective strategy for SCLC treatment, which warrants clinical testing.

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Acknowledgements

We thank Dr Leonard M Neckers for stimulating discussion during the course of the study and Dr Weiwen Ying (Synta Pharmaceuticals) for his valuable comments on the manuscript and for providing ganetespib for the study. This research was funded by the National Cancer Institute Intramural Program.

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Author notes

  1. Current address: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.

Authors and Affiliations

  1. Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    C-H Lai, K-S Park, D-H Lee, A T Alberobello, Y Wang & G Giaccone

  2. Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    M Raffeld

  3. Center for Applied Proteomics and Molecular Medicine, George Masson University, Manassas, VI, USA

    M Pierobon, E Pin & E F Petricoin III

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  1. C-H Lai
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Correspondence to Y Wang or G Giaccone.

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Lai, CH., Park, KS., Lee, DH. et al. HSP-90 inhibitor ganetespib is synergistic with doxorubicin in small cell lung cancer. Oncogene 33, 4867–4876 (2014). https://doi.org/10.1038/onc.2013.439

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