PU-H71: An improvement on nature's solutions to oncogenic Hsp90 addiction

Trendowski, Matthew

doi:10.1016/j.phrs.2015.06.007

Cited by 39 publications

(35 citation statements)

References 152 publications

(224 reference statements)

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“…One reason for this dependence is that cancer cells harbor highly active, cancer cell-specific HSP90 that is present in multi-chaperone complexes, which have a markedly higher affinity towards HSP90 inhibitors than uncomplexed HSP90 in normal cells [31, 32]. In addition, cancer cells are frequently addicted to mutated or overexpressed oncoproteins whose proper folding and function is controlled and maintained by HSP90 [15, 33].…”

Section: Discussionmentioning

confidence: 99%

“…For example, MDR1-overexpressing SW480-R cells show resistance to both PU-H71 and tanespimycin but are sensitive to ganetespib, illustrating that knowledge of MDR1 expression may aid in selecting a specific HSP90 inhibitor. Finally, despite the mixed outcomes of phase 3 clinical trials with MDR1 inhibitors, mostly due to high toxicity in combination with cytotoxic agents, co-administration of PU-H71 and new-generation MDR1 inhibitors may be feasible given the high affinity of PU-H71 for active HSP90 [31, 32] and its specific targeting of complexes comprised of HSP90 and oncogenic fusion proteins in certain cancers [47]. …”

Section: Discussionmentioning

confidence: 99%

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Prospective identification of resistance mechanisms to HSP90 inhibition in KRAS mutant cancer cells

et al. 2016

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Inhibition of the HSP90 chaperone results in depletion of many signaling proteins that drive tumorigenesis, such as downstream effectors of KRAS, the most commonly mutated human oncogene. As a consequence, several small-molecule HSP90 inhibitors are being evaluated in clinical trials as anticancer agents. To prospectively identify mechanisms through which HSP90-dependent cancer cells evade pharmacologic HSP90 blockade, we generated multiple mutant KRAS-driven cancer cell lines with acquired resistance to the purine-scaffold HSP90 inhibitor PU-H71. All cell lines retained dependence on HSP90 function, as evidenced by sensitivity to short hairpin RNA-mediated suppression of HSP90AA1 or HSP90AB1 (also called HSP90α and HSP90β, respectively), and exhibited two types of genomic alterations that interfere with the effects of PU-H71 on cell viability and proliferation: (i) a Y142N missense mutation in the ATP-binding domain of HSP90α that co-occurred with amplification of the HSP90AA1 locus, (ii) genomic amplification and overexpression of the ABCB1 gene encoding the MDR1 drug efflux pump. In support of a functional role for these alterations, exogenous expression of HSP90α Y142N conferred PU-H71 resistance to HSP90-dependent cells, and pharmacologic MDR1 inhibition with tariquidar or lowering ABCB1 expression restored sensitivity to PU-H71 in ABCB1-amplified cells. Finally, comparison with structurally distinct HSP90 inhibitors currently in clinical development revealed that PU-H71 resistance could be overcome, in part, by ganetespib (also known as STA9090) but not tanespimycin (also known as 17-AAG). Together, these data identify potential mechanisms of acquired resistance to small molecules targeting HSP90 that may warrant proactive screening for additional HSP90 inhibitors or rational combination therapies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Prospective identification of resistance mechanisms to HSP90 inhibition in KRAS mutant cancer cells

et al. 2016

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“…The most prominent drugs inhibit the ATPase activity of Hsp90 and are based on the geldanamycin, radicicol, or purine derivatives, which function as competitive inhibitors of ATP binding to Hsp90 (Roe et al, 1999; Sidera and Patsavoudi, 2014). Initial geldanamycin and radicicol derivatives proved to be potent inhibitors of Hsp90; however, their therapeutic value is low due to severe toxicity by targeting Hsp90 in normal cells (Jhaveri et al, 2012; Trendowski, 2015). …”

Section: Hsp90mentioning

confidence: 99%

The Hsp70/Hsp90 Chaperone Machinery in Neurodegenerative Diseases

et al. 2017

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The accumulation of misfolded proteins in the human brain is one of the critical features of many neurodegenerative diseases, including Alzheimer's disease (AD). Assembles of beta-amyloid (Aβ) peptide—either soluble (oligomers) or insoluble (plaques) and of tau protein, which form neurofibrillary tangles, are the major hallmarks of AD. Chaperones and co-chaperones regulate protein folding and client maturation, but they also target misfolded or aggregated proteins for refolding or for degradation, mostly by the proteasome. They form an important line of defense against misfolded proteins and are part of the cellular quality control system. The heat shock protein (Hsp) family, particularly Hsp70 and Hsp90, plays a major part in this process and it is well-known to regulate protein misfolding in a variety of diseases, including tau levels and toxicity in AD. However, the role of Hsp90 in regulating protein misfolding is not yet fully understood. For example, knockdown of Hsp90 and its co-chaperones in a Caenorhabditis elegans model of Aβ misfolding leads to increased toxicity. On the other hand, the use of Hsp90 inhibitors in AD mouse models reduces Aβ toxicity, and normalizes synaptic function. Stress-inducible phosphoprotein 1 (STI1), an intracellular co-chaperone, mediates the transfer of clients from Hsp70 to Hsp90. Importantly, STI1 has been shown to regulate aggregation of amyloid-like proteins in yeast. In addition to its intracellular function, STI1 can be secreted by diverse cell types, including astrocytes and microglia and function as a neurotrophic ligand by triggering signaling via the cellular prion protein (PrPC). Extracellular STI1 can prevent Aβ toxic signaling by (i) interfering with Aβ binding to PrPC and (ii) triggering pro-survival signaling cascades. Interestingly, decreased levels of STI1 in C. elegans can also increase toxicity in an amyloid model. In this review, we will discuss the role of intracellular and extracellular STI1 and the Hsp70/Hsp90 chaperone network in mechanisms underlying protein misfolding in neurodegenerative diseases, with particular focus on AD.

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“…In contrast, the Charité Onkologie (CONKO)-004 trial selected patients with advanced pancreatic cancer, a malignancy associated with the highest VTE rates, and demonstrated a clinically significant absolute reduction in VTE risk from 15.1% to 6.4% in control vs treated patients. 9 Although VTE is a relatively rare event, breast cancer is the most common cancer in women worldwide. Thus, the question of whether to use thromboprophylaxis to reduce breast cancer-related VTE has a substantial clinical impact.…”

mentioning

confidence: 99%

“…Tumor cells frequently contain relatively high levels of a "stress active" form of Hsp90 termed TEHsp90, which is required to maintain malignant cell viability and proliferation. Hsp90 inhibitors, including PU-H71, have shown promising preclinical activity in B-cell malignancies; 9 however, cellular responses are typically limited by feedback induction of another chaperone, Hsp70B. CuljkovicKraljacic et al showed that eIF4E was a TEHsp90 client protein in BCL cell lines and that, in turn, eIF4E was required for PU-H71-induced Hsp70B expression.…”

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confidence: 99%

Shooting the messenger (RNA) in B-cell lymphoma

Yeomans

Packham

2016

Blood

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Despite the morbidity and mortality associated with VTE in cancer patients, current clinical practice guidelines do not recommend routine thromboprophylaxis in outpatients with cancer. 5,6 The relatively low overall rate of VTE among breast cancer patients, ,1%/year in this study population, does not justify the notion of population-wide thromboprophylaxis given the risk of serious treatment-related adverse events such as major bleeding. A significant challenge is identifying the patients at moderate to high risk for VTE who are most likely to benefit from primary thromboprophylaxis treatment.Because the net benefit of therapies involving treatment-related harm depends on the likelihood of the outcome, a trial enrolling patients without a risk-based sampling strategy or subgroup analysis is unlikely to yield favorable summary results. 7 The Evaluation of AVE5026in the Prevention of Venous Thromboembolism in Cancer Patients Undergoing Chemotherapy trial demonstrated a large relative effect size (nearly threefold higher VTE risk in placebo vs semuloparin treated), but a small absolute risk reduction in VTE of only 2.2% (3.2% and 1.4% in control and treatment groups, respectively). 8Absolute risk reductions of this magnitude are not enough to counterbalance potential treatment related harms, assuming a 1% risk of intracranial hemorrhage. In contrast, the Charité Onkologie (CONKO)-004 trial selected patients with advanced pancreatic cancer, a malignancy associated with the highest VTE rates, and demonstrated a clinically significant absolute reduction in VTE risk from 15.1% to 6.4% in control vs treated patients. 9Although VTE is a relatively rare event, breast cancer is the most common cancer in women worldwide. Thus, the question of whether to use thromboprophylaxis to reduce breast cancer-related VTE has a substantial clinical impact. The findings by Walker et al suggest that the future of thromboprophylaxis in breast cancer patients should be time-limited treatment of those at highest risk. Selectively applying thromboprophylaxis to those patients at highest risk and, critically, only while those patients are at risk, may limit overtreatment of patients unlikely to benefit while avoiding the majority of adverse outcomes. Recognition of the time-sensitive nature of VTE risk associated with surgery and treatments could be leveraged to improve risk prediction algorithms to better identify candidates for thromboprophylaxis. Future studies are needed to evaluate how these results may be used to more precisely target patients with the best chance of benefiting from new and existing therapies. The current study provides valuable evidence that can both inform this future research and be used for counseling patients about VTE risk. Women with breast cancer undergoing surgery, chemotherapy, or hormonal therapy have a specific time interval during which they are at increased risk of VTE. Discussion of common VTE symptoms should therefore be included, alongside admonitions on neutropenic fevers and more common treatment sid...

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PU-H71: An improvement on nature's solutions to oncogenic Hsp90 addiction

Cited by 39 publications

References 152 publications

Prospective identification of resistance mechanisms to HSP90 inhibition in KRAS mutant cancer cells

Prospective identification of resistance mechanisms to HSP90 inhibition in KRAS mutant cancer cells

The Hsp70/Hsp90 Chaperone Machinery in Neurodegenerative Diseases

Shooting the messenger (RNA) in B-cell lymphoma

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