Author of

• 14739

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  MINI 14 - Pre-Clinical Therapy (ID 119)

  • Event: WCLC 2015
  • Type: Mini Oral
  • Track: Biology, Pathology, and Molecular Testing
  • Presentations: 1
  • Moderators:L. Fernandez-Cuesta, A.F. Gazdar
  • Coordinates: 9/08/2015, 10:45 - 12:15, Mile High Ballroom 2c-3c

  • 14747

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    MINI14.08 - HSP90 Inhibitor Ganetespib Radiosensitizes Human Lung Adenocarcinoma Cells and Inhibits Lung Cancer Stem Cells (ID 2789)

    11:25 - 11:30  |  Author(s): D. Proia
    • Abstract
    • Presentation
    • Slides

    Background:
    Ionizing radiation (IR) therapy is an integral component of treatment for NSCLC, however, the majority of patients succumb to this disease as the disease tends to relapse and metastasize. The failure of the therapies is associated with hypermalignant cancer-initiating cells (CICs). CICs are radiation-resistant; therefore, targeting CICs represent an important therapeutic strategy for improving the outcome of IR treatment. Ganetespib, a novel heat shock protein 90 (HSP90) inhibitor, reduces expression of multiple HSP90-dependent client oncoproteins. We evaluated both the in vitro and in vivo antitumor effects of ganetespib, in combination with IR, in human lung adenocarcinoma (AC) cells.
    
    Methods:
    The radiosentisizing activity of ganetespib, HSP90 inhibitor, was evaluated in human lung AC cells established from surgical tumor samples.
    
    Results:
    Ganetespib inhibits growth of bulk AC cells, as well as lung CICs, growing as tumor spheres. The cytotoxic effects of ganetespib G2/M cell cycle DNA repair, apoptosis, and senescence. All of these antitumor effects were both concentration- and time-dependent. At the molecular level, ganetespib inhibited pro-survival signaling in adenocarcinoma cells through decreased p-AKT expression, the downregulation of RAD51 and the upregulation of p21. Ganetespib, at low nanomolar concentrations sensitizes AC to IR treatment. Importantly, both pretreatment and post –radiation treatment (24h after IR) with ganetespib (3nM) could dramatically augment the antitumor effects of IR decreasing the survival rate of IR-treated cells. Our study suggests that ganetespib may impart radiosensitization through multiple mechanisms: such as the down regulation of the PI3K/Akt pathway; diminished DNA repair capacity and the promotion of cellular senescence. In vivo, ganetespib was effective in reducing the tumor growth of primary T2821 tumor xenografts in mice and sensitized tumors to IR.
    
    Conclusion:
    The HSP90 inhibitor, ganetespib, potentiates the effect of IR in NSCLC and eliminates CICs. The radiosensitizing effect of ganetespib is mediated by the combinatorial inhibition of cell growth and survival pathways. Ganetespib is the most potent HSP90-mediated radiosensitizer yet reported in vitro, and for the first time validated in a clinically relevant in vivo model. The use of ganetespib as a therapeutic warrants a further investigation in the clinical setting.
    
    

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