Background: Ganetespib (STA-9090) has anticancer activity due to inhibition of the chaperoning activity of HSP90 for oncogenes and other cellular proteins which support malignant growth. Especially, clinical activity as single drug was found in tumors addicted to modified kinases, such as HER2, ALK, BRAF, KIT and others. In the present work we tested the cytotoxic effects of ganetespib either alone or in combination with chemotherapeutics against a panel of small cell lung cancer cell lines.
Methods: Cytotoxicity was assessed using MTT assays, cell cycle effects by propidium iodide staining, HSP90 expression by flow cytometry and synergism of drug combinations was calculated employing the Chou-Talalay method.
Results: The chemoresistant small cell lung cancer (SCLC) cell lines GLC16, NCI-H417 and DMS153 were highly sensitive to ganetespib (IC50 <30 nM), whereas chemosensitive GLC14 and primary SCLC26A cells exhibited chemoresistance to this drug. Ganetespib showed marked synergy in combination with cisplatin/carboplatin, etoposide and doxorubicin, whereas limited cooperative effects were observed for topotecan and the cisplatin/etoposide triple combination. Determinations of HSP90 expression using a monoclonal antibody pointed to an association of the cytotoxic effects of ganetespib with cell surface expression of this target and not with total expression of this heat shock protein.
Conclusions: In contrast to the first-generation HSP90 inhibitors, such as geldanamycin or 17-N-allylamino-17-demethoxygeldanamycin (17AAG), ganetespib has a far more favorable safety profile and has shown clinical anticancer activity in breast cancer, non-small cell lung cancer (NSCLC), gastrointestinal stromal tumors (GIST) and various hematological malignancies. According to our results, ganetespib is not expected to be active against primary, untreated SCLCs as single drug; however, is estimated to show cytotoxicity for pretreated SCLCs, either alone or in combinations with platinum drugs, etoposide or doxorubicin. These in vitro results are compatible with inhibition of an HSP90 client protein by ganetespib which is induced in response to prior exposure of the cells to chemotherapy in vivo.
