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

Lazenby, Michelle; Hills, Robert Kerrin; Burnett, Alan Kenneth; Zabkiewicz, Joanna

doi:10.1016/j.leukres.2015.03.016

Cited by 27 publications

(28 citation statements)

References 42 publications

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“…The capacity of inhibitors of Hsp90 to block kinase‐mediated intracellular signaling pathways and the increasing availability of natural and synthetic pharmacologic inhibitors of Hsp90 have made Hsp90 an attractive therapeutic target in a variety of cancers including breast and lung cancers, as well as a variety of hematologic malignancies . These same pathways signal for de novo inflammatory gene expression in cells of the innate immune system, suggesting a potential role for Hsp90 inhibition in a variety of acute and chronic inflammatory disorders.…”

Section: Discussionmentioning

confidence: 99%

Heat-shock protein-90 prolongs septic neutrophil survival by protecting c-Src kinase and caspase-8 from proteasomal degradation

Gupta

Lee

Wang

et al. 2018

Journal of Leukocyte Biology

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The brief lifespan of the polymorphonuclear neutrophil (PMN) is regulated through its capacity to undergo apoptosis, a constitutive process that is actively inhibited during sepsis. We sought to define the cellular mechanisms through which Heat Shock Protein 90 (Hsp90) prolongs the survival of inflammatory PMN. We evaluated Hsp90 expression and interaction with client proteins in PMNs from patients with sepsis and in healthy control PMNs treated with LPS (1 μg/mL). Hsp90 activity was inhibited pharmacologically using radicicol (Rad; 1 μM), and Hsp90 transcription was silenced in septic PMN using siRNA. PMN apoptosis was evaluated by flow cytometry and expression of cleaved caspase-8 and -3. Septic PMNs showed reduced rates of apoptosis compared with control PMNs 21 h after isolation, and Hsp90-α mRNA was significantly more abundant in septic PMN. Caspase-8 coimmunoprecipitated with Hsp90, c-Src, and the p85 inhibitory subunit of PI3K in both septic and LPS-treated PMN. Inhibition of Hsp90 activity with Rad or its translation using siRNA restored basal rates of apoptosis in both septic and LPS-treated PMN. Radicicol further reduced c-Src protein abundance, increased the ubiquitination of caspase-8 and c-Src, and enhanced the cleavage of caspase-8 and -3. We conclude that Hsp90 prolongs the survival of activated neutrophils by stabilizing a molecular complex of c-Src kinase and caspase-8, preventing their ubiquitination, and resulting in inhibition of the catalytic activity of caspase-8 and -3.

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Section: Discussionmentioning

confidence: 99%

Heat-shock protein-90 prolongs septic neutrophil survival by protecting c-Src kinase and caspase-8 from proteasomal degradation

Gupta

Lee

Wang

et al. 2018

Journal of Leukocyte Biology

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“…Ganetespib, an HSP90 inhibitor, has been shown to induce growth arrest and apoptosis in various cancer models . In several clinical trials, ganetespib has not only demonstrated an antitumour effect, but also caused few side‐effects .…”

Section: Discussionmentioning

confidence: 99%

“…Numerous clinical trials are currently testing HSP90 inhibitors against different types of cancer . Ganetespib, a novel HSP90 inhibitor, exerts its competitive inhibitory effect by binding to the N‐terminal ATP‐binding site, and has been shown to have antitumour activity and lower hepatic and ocular toxicity compared with other HSP90 inhibitors . In addition, HSP90 inhibitors have attracted attention as sensitizers of cancer cells to both conventional chemotherapy and radiation therapy .…”

mentioning

confidence: 99%

Inhibition of heat shock protein 90 exerts an antitumour effect in angiosarcoma: involvement of the vascular endothelial growth factor signalling pathway

et al. 2017

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“…Targeted inhibition of Hsp90 is quite effective in preclinical studies involving KRAS mutant NSCLC cell lines and mouse models (9,27,50). However, Hsp90i such as ganetespib, which showed strong preclinical efficacy, both in monotherapy or with chemotherapy (9,27,51), had little activity in patients with KRAS mutant tumors (11,12). Furthermore, the combination of ganetespib and docetaxel, which was recently tested in a large phase III clinical trial (Galaxy-2) in advanced lung cancer, failed to demonstrate either a PFS or OS benefit in either KRAS mutant or KRAS wild type NSCLC patients (29).…”

Section: Discussionmentioning

confidence: 99%

Reactivation of the p90RSK–CDC25C Pathway Leads to Bypass of the Ganetespib-Induced G2–M Arrest and Mediates Acquired Resistance to Ganetespib inKRAS-Mutant NSCLC

Chatterjee

Huang

Christie

et al. 2017

Molecular Cancer Therapeutics

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A subset of non-small cell lung cancers (NSCLC) are dependent upon oncogenic driver mutations including the most frequently observed driver mutant KRAS which is associated with a poor prognosis. As direct RAS targeting in the clinic has been unsuccessful to date, use of Heat shock protein 90 (Hsp90) inhibitors appeared to be a promising therapy for KRAS mutant NSCLC, however limited clinical efficacy was observed due to rapid resistance. Furthermore, the combination of the Hsp90 inhibitor (Hsp90i), ganetespib and docetaxel was tested in a phase III clinical trial and failed to demonstrate benefit. Here, we investigated the mechanism(s) of resistance to ganetespib and explored why the combination with docetaxel failed in the clinic. We have not only identified a critical role for the bypass of the G2/M cell cycle checkpoint as a mechanism of ganetespib resistance (GR) but have also found that GR leads to cross-resistance to docetaxel. Reactivation of p90RSK and its downstream target, CDC25C was critical for GR and mediated the bypass of a G2/M arrest. Overexpression of either p90RSK or CDC25C lead to bypass of G2/M arrest and induced ganetespib resistance in vitro and in vivo. Moreover, resistance was dependent on p90RSK/CDC25C signaling, as synthetic lethality to ERK1/2, p90RSK or CDC25C inhibitors was observed. Importantly, the combination of ganetespib and p90RSK or CDC25C inhibitors was highly efficacious in parental cells. These studies provide a way forward for Hsp90 inhibitors through the development of novel rationally designed Hsp90 inhibitor combinations that may prevent or overcome resistance to Hsp90i.

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

Cited by 27 publications

References 42 publications

Heat-shock protein-90 prolongs septic neutrophil survival by protecting c-Src kinase and caspase-8 from proteasomal degradation

Heat-shock protein-90 prolongs septic neutrophil survival by protecting c-Src kinase and caspase-8 from proteasomal degradation

Inhibition of heat shock protein 90 exerts an antitumour effect in angiosarcoma: involvement of the vascular endothelial growth factor signalling pathway

Reactivation of the p90RSK–CDC25C Pathway Leads to Bypass of the Ganetespib-Induced G2–M Arrest and Mediates Acquired Resistance to Ganetespib inKRAS-Mutant NSCLC

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