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HSP90 is a multi-client chaperone involved in regulating a large array of cellular processes and is commonly overexpressed in many different cancer types including hematological malignancies. Inhibition of HSP90 holds promise for targeting multiple molecular abnormalities and is therefore an attractive target for heterogeneous malignancies such as Acute Myeloid Leukemia (AML). Ganetespib is a highly potent second generation HSP90 inhibitor which we show is significantly more effective against primary AML blasts at nanomolar concentrations when compared with cytarabine (p<0.001). Dose dependant cytotoxicity was observed with an apoptotic response coordinate with the loss of pro-survival signaling through the client protein AKT. Combination treatment of primary blasts with ganetespib and cytarabine showed good synergistic interaction (combination index (CI): 0.47) across a range of drug effects with associated reduction in HSP70 feedback and AKT signaling levels. In summary, we show ganetespib to have high activity in primary AMLs as a monotherapy and a synergistic relationship with cytarabine when combined. The combination of cytotoxic cell death, suppression of cytoprotective/drug resistance mechanisms such as AKT and reduced clinical toxicity compared to other HSP90 inhibitors provide strong rationale for the clinical assessment of ganetespib in AML.

Original publication

DOI

10.1016/j.leukres.2015.03.016

Type

Journal article

Journal

Leuk Res

Publication Date

06/2015

Volume

39

Pages

617 - 624

Keywords

AML, Ganetespib, HSP90, Antineoplastic Combined Chemotherapy Protocols, Blast Crisis, Cytarabine, Dose-Response Relationship, Drug, Female, HL-60 Cells, HSP90 Heat-Shock Proteins, Humans, Leukemia, Myeloid, Acute, Male, Proto-Oncogene Proteins c-akt, Triazoles