title: HSP-90 inhibitor ganetespib is synergistic with doxorubicin in small cell lung cancer.
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.
authors.affiliation: 1] Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA [2].
authors.forename: C-H
authors.initials: CH
authors.lastname: Lai
authors.affiliation: Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: K-S
authors.initials: KS
authors.lastname: Park
authors.affiliation: Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: D-H
authors.initials: DH
authors.lastname: Lee
authors.affiliation: Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: A T
authors.initials: AT
authors.lastname: Alberobello
authors.affiliation: Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: M
authors.initials: M
authors.lastname: Raffeld
authors.affiliation: Center for Applied Proteomics and Molecular Medicine, George Masson University, Manassas, VI, USA.
authors.forename: M
authors.initials: M
authors.lastname: Pierobon
authors.affiliation: Center for Applied Proteomics and Molecular Medicine, George Masson University, Manassas, VI, USA.
authors.forename: E
authors.initials: E
authors.lastname: Pin
authors.affiliation: Center for Applied Proteomics and Molecular Medicine, George Masson University, Manassas, VI, USA.
authors.forename: E F
authors.initials: EF
authors.lastname: Petricoin Iii
authors.affiliation: Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: G
authors.initials: G
authors.lastname: Giaccone
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology* / Q000627:therapeutic use; D004357:Drug Synergism; D059565:G2 Phase Cell Cycle Checkpoints; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000473:pathology; D014230:Triazoles / Q000494:pharmacology* / Q000627:therapeutic use; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D018841:HSP90 Heat-Shock Proteins; C533237:STA 9090; D014230:Triazoles; D004317:Doxorubicin