The HSP90 Inhibitor Ganetespib Synergizes With The Lapatinib In HER2-positive Breast Cancers

Objective: To study the mechanism of the HSP90 inhibitor ganetespib in combination with lapatinib against HER2-overexpression breast cancer cells.Methods: MTT assay was used to assess cell proliferation inhibition;Western blot was applied to reveal the protein expression of related proliferous and apoptotic signaling pathway;The apoptotic induction was detected by flow cytometry;Synergy was evaluated using the Compu Syn Software;Protein-protein interactions was showed by co-immunoprecipitation.Results: lapatinib failed to induce sustained inhibition of HER3 signaling in HER2-driven breast cancer cells;The HSP90 inhibitor ganetespib synergized with the lapatinib to inhibit cell proliferation and to induce cell apoptosis in HER2-driven cancer;The conbination of ganetespib and lapatinib could dissociate Hsp90/HER3chaperon/ co-chaperon complex,followed by degradation of the Hsp90 client proteins,for example HER3;The conbination of ganetespib and lapatinib succeded to induce sustained inhibition of HER3 signaling in HER2-driven breast cancer cells.Conclusion: The conbination of ganetespib and lapatinib displayed potent antitumor effect in suppression of proliferation and apoptosis HER2-driven breast cancer cells by succeding to induce sustained inhibition of HER3 signaling.