Inhibition of HSP90 molecular chaperones: moving into the clinic

Garcia-Carbonero, Rocío; Carnero, Amancio; Paz‐Ares, Luis

doi:10.1016/s1470-2045(13)70169-4

Cited by 318 publications

(357 citation statements)

References 64 publications

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“…HSP90 is an actively pursued target in oncology; however, no selective agents have yet been approved for human therapeutic use. HSP90 inhibitors, including ganetespib, have shown encouraging single-agent efficacy in early-stage clinical trials, most commonly in molecularly defined subgroups of tumors that are oncogenically "addicted" to specific client proteins, for example, ALK-rearranged NSCLC and HERamplified breast cancer (5,31,32). More typically, however, the results obtained for HSP90-directed monotherapy in unselected patient populations have proven less definitive (33).…”

Section: Discussionmentioning

confidence: 99%

mTOR Inhibition Potentiates HSP90 Inhibitor Activity via Cessation of HSP Synthesis

Acquaviva

Sang

et al. 2014

Molecular Cancer Research

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Because of their pleiotropic effects on critical oncoproteins, inhibitors of HSP90 represent a promising new class of therapeutic agents for the treatment of human cancer. However, pharmacologic inactivation of HSP90 subsequently triggers a heat shock response that may mitigate the full therapeutic benefit of these compounds. To overcome this limitation, a clinically feasible method was sought to block HSP synthesis induced by the potent HSP90 inhibitor ganetespib. An immunoassay screen of 322 late-stage or clinically approved drugs was performed to uncover compounds that could block upregulation of the stress-inducible HSP70 that results as a consequence of HSP90 blockade. Interestingly, inhibitors of the phosphoinositide 3-kinase (PI3K)/mTOR class counteracted ganetespibinduced HSP70 upregulation at both the gene and protein level by suppressing nuclear translocation of heat shock factor 1 (HSF1), the dominant transcription factor controlling cellular stress responses. This effect was conserved across multiple tumor types and was found to be regulated, in part, by mTOR-dependent translational activity. Pretreatment with cycloheximide, PI3K/mTOR inhibitor, or an inhibitor of eIF4E (a translation initiation factor and downstream effector of mTOR) all reduced ganetespib-mediated nuclear HSF1 accumulation, indicating that mTOR blockade confers a negative regulatory effect on HSF1 activity. Moreover, combined therapy regimens with mTOR or dual PI3K/mTOR inhibitors potentiated the antitumor efficacy of ganetespib in multiple in vivo models.

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Section: Discussionmentioning

confidence: 99%

mTOR Inhibition Potentiates HSP90 Inhibitor Activity via Cessation of HSP Synthesis

Acquaviva

Sang

et al. 2014

Molecular Cancer Research

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“…For example, NVP-AUY922 is active against ALK-TKI-or EGFR-TKI-resistant non-small cell lung carcinoma (8,38). However, because HSP90 also plays a role in normal cells, it is essential to balance efficacy and toxicity to maximize the antitumor potential of HSP90 inhibitors.…”

Section: Discussionmentioning

confidence: 99%

“…HSP90 is reported to be specifically overexpressed (4,5) and to exist as activated multi-chaperone complexes in cancer cells and cancer tissues (6,7); indeed, it has been proposed that cancers are highly "addicted" to HSP90 for their survival and proliferation (1). HSP90 has therefore emerged as an attractive target for cancer interventions, and many HSP90 inhibitors have been developed (8).…”

Section: Introductionmentioning

confidence: 99%

“…Though HSP90 inhibitors have been shown in different preclinical models to exert their potent antitumor activities by destabilizing HSP90 clients (9-13), they have also been shown to have limited single-agent activity in the clinical setting (3,8,14). One explanation for this discrepancy may be that the levels of drug exposure reached in patients are insufficient to effectively inhibit tumor cell HSP90 because of undesirable offtarget and/or HSP90-related adverse events.…”

Section: Introductionmentioning

confidence: 99%

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TAS-116, a Highly Selective Inhibitor of Heat Shock Protein 90α and β, Demonstrates Potent Antitumor Activity and Minimal Ocular Toxicity in Preclinical Models

Ohkubo

Kodama

Muraoka

et al. 2015

Molecular Cancer Therapeutics

100

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The molecular chaperone HSP90 plays a crucial role in cancer cell growth and survival by stabilizing cancer-related proteins. A number of HSP90 inhibitors have been developed clinically for cancer therapy; however, potential off-target and/or HSP90-related toxicities have proved problematic. The 4-(1H-pyrazolo [3,4-b]pyridine-1-yl)benzamide TAS-116 is a selective inhibitor of cytosolic HSP90a and b that does not inhibit HSP90 paralogs such as endoplasmic reticulum GRP94 or mitochondrial TRAP1. Oral administration of TAS-116 led to tumor shrinkage in human tumor xenograft mouse models accompanied by depletion of multiple HSP90 clients, demonstrating that the inhibition of HSP90a and b alone was sufficient to exert antitumor activity in certain tumor models. One of the most notable HSP90-related adverse events universally observed to differing degrees in the clinical setting is visual disturbance. A two-week administration of the isoxazole resorcinol NVP-AUY922, an HSP90 inhibitor, caused marked degeneration and disarrangement of the outer nuclear layer of the retina and induced photoreceptor cell death in rats. In contrast, TAS-116 did not produce detectable photoreceptor injury in rats, probably due to its lower distribution in retinal tissue. Importantly, in a rat model, the antitumor activity of TAS-116 was accompanied by a higher distribution of the compound in subcutaneously xenografted NCI-H1975 non-small cell lung carcinoma tumors than in retina. Moreover, TAS-116 showed activity against orthotopically transplanted NCI-H1975 lung tumors. Together, these data suggest that TAS-116 has a potential to maximize antitumor activity while minimizing adverse effects such as visual disturbances that are observed with other compounds of this class.

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“…Drug 'gedunin' binds to P23 and restores the apoptotic pathways of malignant cells [23]. Drugs like Retaspimycin (IPI-504), Ganetespib (STA-9090) are candidates in the on going phase 1-3 clinical trials targeting Hsp 90 in various cancers [24].…”

Section: Hsp90mentioning

confidence: 99%