The HSP90 inhibitor ganetespib: A potential effective agent for Acute Myeloid Leukemia in combination with cytarabine

M Lazenby,R Hills,A.K Burnett,J Zabkiewicz

doi:10.1016/j.leukres.2015.03.016

M Lazenby, R Hills + Show 2 more

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https://doi.org/10.1016/j.leukres.2015.03.016

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Journal: Leukemia Research	Publication Date: Mar 30, 2015
Citations: 27	License type: cc-by

Affiliation: Cardiff University

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.

Highlights

Heat shock protein 90 (HSP90) is a key member of the heat shock protein family which act as molecular chaperones, facilitating protein folding and activation of client proteins that cover a diverse range of cellular functions including signal transduction via protein kinases, chromatin/epigenetic remodeling, vesicular transport, immune response, steroid signaling and regulation of viral infections [1,2,3]
This study demonstrates that the novel HSP90 inhibitor, ganetespib, is an effective agent against primary AML blasts at nanomolar concentrations which are clinically achievable [21] and far superior to the standard agent, cytarabine
The clinical development of many HSP90 inhibitors has been limited by toxicities, ocular toxicity [13,29], but the clinical development of ganetespib to date suggests that the drug is well tolerated and that the ocular toxicity is infrequent, in contrast to some other second generation HSP90 inhibitors [16,20,21]

Summary

Introduction

Heat shock protein 90 (HSP90) is a key member of the heat shock protein family which act as molecular chaperones, facilitating protein folding and activation of client proteins that cover a diverse range of cellular functions including signal transduction via protein kinases, chromatin/epigenetic remodeling, vesicular transport, immune response, steroid signaling and regulation of viral infections [1,2,3]. HSP90 acts as a chaperone to a large number of client proteins including SRC, KIT, RAL, JAK, AKT, ERBB2 and CDKs, many of which are oncogenically activated in cancer cells [13]. Cell survival and tumor progression may be critically dependent upon HSP90 function through the chaperones ability to protect mutant and oncogenic proteins from degradation. Given the molecular heterogeneity of AML, HSP90 inhibition could represent a logical therapeutic strategy

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