title: The HSP90 inhibitor ganetespib: A potential effective agent for Acute Myeloid Leukemia in combination with cytarabine.
abstract: 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.
authors.affiliation: Cardiff Experimental Cancer Medicine Centre (ECMC), Department of Haematology, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: M
authors.initials: M
authors.lastname: Lazenby
authors.affiliation: Cardiff Experimental Cancer Medicine Centre (ECMC), Department of Haematology, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: R
authors.initials: R
authors.lastname: Hills
authors.affiliation: Cardiff Experimental Cancer Medicine Centre (ECMC), Department of Haematology, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: A K
authors.initials: AK
authors.lastname: Burnett
authors.affiliation: Cardiff Experimental Cancer Medicine Centre (ECMC), Department of Haematology, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK. Electronic address: ZabkiewiczJ1@Cardiff.ac.uk.
authors.forename: J
authors.initials: J
authors.lastname: Zabkiewicz
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001752:Blast Crisis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003561:Cytarabine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D018922:HL-60 Cells; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology
chemical_list: D018841:HSP90 Heat-Shock Proteins; C533237:STA 9090; D014230:Triazoles; D003561:Cytarabine; D051057:Proto-Oncogene Proteins c-akt
keywords: AML; Ganetespib; HSP90