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Heat shock protein 90 (Hsp90) is an ATP-dependent molecular chaperone which is essential in eukaryotes. It is required for the activation and stabilization of a wide variety of client proteins and many of them are involved in important cellular pathways. Since Hsp90 affects numerous physiological processes such as signal transduction, intracellular transport, and protein degradation, it became an interesting target for cancer therapy. Structurally, Hsp90 is a flexible dimeric protein composed of three different domains which adopt structurally distinct conformations. ATP binding triggers directionality in these conformational changes and leads to a more compact state. To achieve its function, Hsp90 works together with a large group of cofactors, termed co-chaperones. Co-chaperones form defined binary or ternary complexes with Hsp90, which facilitate the maturation of client proteins. In addition, posttranslational modifications of Hsp90, such as phosphorylation and acetylation, provide another level of regulation. They influence the conformational cycle, co-chaperone interaction, and inter-domain communications. In this review, we discuss the recent progress made in understanding the Hsp90 machinery.

Targeted therapies for melanoma MEK and BRAF inhibitors fail due to the development of chemoresistance. As Hsp90 inhibitors target client proteins of resistant pathways, we hypothesised that C‐terminal Hsp90 inhibitors will target BRAF/MEK inhibitor resistant melanoma cells by overcoming the resistant pathways. Two melanoma cell lines, A375 and A375 MEK/BRAF inhibitor resistant (A375MEKi) were utilised. The inhibitory concentrations (IC50) of two C‐terminal Hsp90 inhibitors, KU757 and KU758, were determined by CellTiter Glo. RNA sequencing was performed after treatment with KU757. Pathways targeted by differentially expressed genes were evaluated by David, IPA, GSEA, and by evaluating the cell cycle, apoptosis and oxidative phosphorylation. Expression levels of hub genes were evaluated using Xena and validated by RT‐PCR. The survival analysis was performed using UALCAN. A375MEKi was not resistant to the C‐terminal Hsp90 inhibitor with a KU757 IC50 of 0.59 μM versus 0.64 μM and a KU758 IC50 of 0.89 μM versus 0.93 μM in A375 versus A375MEKi, respectively. RNA sequencing analysis revealed KU757 upregulates cell cycle checkpoint regulation and apoptosis and downregulates genes involved in the peroxisome, AKT/PI3K/MTOR, EIF2, fatty acid metabolism and oxidative phosphorylation. These pathways were further validated through survival analysis that demonstrated potential survival benefit in patients with dysregulated NDUFA7, CDC20, CDC25C, CDK1, VDAC2, HEATR5a, COL4A4, FLT3LG, BMP2, PRKCH and ADMST9. Melanomas often develop concurrent resistance to BRAF and MEK inhibitors. C‐terminal Hsp90 inhibition with KU757 appears to overcome these chemo‐resistance pathways in vitro, downregulating metabolic pathways including oxidative phosphorylation and the cell cycle, warranting further in vivo translation. The novel C‐terminal HSP90 inhibitor KU757 effectively targets primary and BRAF and MEK inhibitor‐resistant melanoma cells equally by affecting oxidative phosphorylation and the cell cycle.

The evolutionary conserved molecular chaperone heat shock protein 90 (HSP90) plays an indispensable role in tumorigenesis by stabilizing client oncoproteins. Although the functionality of HSP90 is tightly regulated, cancer cells exhibit a unique dependence on this chaperone, leading to its overexpression, which has been associated with poor prognosis in certain malignancies. While various strategies targeting heat shock proteins (HSPs) involved in carcinogenesis have been explored, only inhibition of HSP90 has consistently and effectively resulted in proteasomal degradation of its client proteins. To date, a total of 22 HSP90 inhibitors (HSP90i) have been tested in 186 cancer clinical trials, as reported by clinicaltrials. gov. Among these trials, 60 % have been completed, 10 % are currently active, and 30 % have been suspended, terminated, or withdrawn. HSP90 inhibitors (HSP90i) have been used as single agents or in combination with other drugs for the treatment of various cancer types in clinical trials. Notably, improved clinical outcomes have been observed when HSP90i are used in combination therapies, as they exhibit a synergistic antitumor effect. However, as single agents, HSP90i have shown limited clinical activity due to drug-related toxicity or therapy resistance. Recently, active trials conducted in Japan evaluating TAS-116 (pimitespib) have demonstrated promising results with low toxicity as monotherapy and in combination with the immune checkpoint inhibitor nivolumab. Exploratory biomarker analyses performed in various trials have demonstrated target engagement that suggests the potential for identifying patient populations that may respond favorably to the therapy. In this review, we discuss the advances made in the past 5 years regarding HSP90i and their implications in anticancer therapeutics. Our focus lies in evaluating drug efficacy, prognosis forecast, pharmacodynamic biomarkers, and clinical outcomes reported in published trials. Through this comprehensive review, we aim to shed light on the progress and potential of HSP90i as promising therapeutic agents in cancer treatment.

Targeting the heat shock protein-90 (Hsp90) chaperone machinery in various cancers with 200 monotherapy or combined-therapy clinical trials since 1999 has not yielded any success of food and drug administration approval. Blames for the failures were unanimously directed at the Hsp90 inhibitors or tumors or both. However, analyses of recent cellular and genetic studies together with the Hsp90 data from the Human Protein Atlas database suggest that the vast variations in Hsp90 expression among different organs in patients might have been the actual cause. It is evident now that Hsp90β is the root of dose-limiting toxicity (DLT), whereas Hsp90α is a buffer of penetrated Hsp90 inhibitors. The more Hsp90α, the safer Hsp90β, and the lower DLT are for the host. Unfortunately, the dramatic variations of Hsp90, from total absence in the eye, muscle, pancreas, and heart to abundance in reproduction organs, lung, liver, and gastrointestinal track, would cause the selection of any fair toxicity biomarker and an effective maximum tolerable dose (MTD) of Hsp90 inhibitor extremely challenging. In theory, a safe MTD for the organs with high Hsp90 could harm the organs with low Hsp90. In reverse, a safe MTD for organs with low or undetectable Hsp90 would have little impact on the tumors, whose cells exhibit average 3–7% Hsp90 over the average 2–3% Hsp90 in normal cells. Moreover, not all tumor cell lines tested follow the “inhibitor binding-client protein degradation” paradigm. It is likely why the oral Hsp90 inhibitor TAS-116 (Pimitespib), which bypasses blood circulation and other organs, showed some beneficiary efficacy by conveniently hitting tumors along the gastrointestinal track. The critical question is what the next step will be for the Hsp90 chaperone as a cancer therapeutic target.

Heat shock protein 90 (HSP90) serves as a central orchestrator of oncogenic protein homeostasis, empowering tumor progression, metastasis, and therapy resistance. However, the clinical translation of HSP90 inhibition has been hampered by challenges such as intrinsic and acquired resistance, a lack of reliable biomarkers, and the toxicity associated with pan-inhibitors. This review comprehensively dissects these challenges and presents the evolving landscape of strategies to overcome them. We systematically catalog the development of over 20 representative HSP90 inhibitors, from classical N-terminal ATP-competitive agents to novel C-terminal and middle-domain binders, highlighting their distinct mechanisms and the rise of subtype-selective compounds designed to enhance therapeutic windows. Beyond monotherapy, we emphasize the paradigm shift towards combination regimens, detailing synergistic effects with chemotherapy, targeted agents, and immunotherapies that resensitize tumors to treatment. Critically, we explore the diagnostic frontier, reviewing how radiolabeled HSP90 inhibitors (e.g., [¹²⁴I]PU-H71 and [¹⁸F]San A derivatives) enable non-invasive tumor detection and patient stratification through positron emission tomography (PET). Finally, we chart the future course of the field, underscoring how precision medicine approaches—guided by biomarker identification and liquid biopsy—coupled with nanotechnology-driven delivery systems, are poised to unlock the full potential of HSP90-targeted cancer theranostics. This synthesis provides not only a mechanistic overview but also a strategic roadmap for the next generation of HSP90-directed oncology research.

Heat shock protein 90 (Hsp90) stabilizes numerous oncogenic proteins, making it a key therapeutic target in cancer. This protocol details an ex vivo method using freshly resected human renal cell carcinoma tissues to evaluate fluorescently labeled Hsp90 inhibitor ganetespib accumulation in tumor versus normal tissue. By preserving the native tumor architecture, this method offers a physiologically relevant alternative to xenograft models. This protocol combines flow cytometry and confocal microscopy to quantitatively and visually assess ganetespib uptake, providing insight into drug distribution and therapeutic response in human cancers. For complete details on the use and execution of this protocol, please refer to Dunn et al. and Woodford et al.

Breast cancer, the most invasive cancer in women globally, necessitates novel treatments due to prevailing limitations of therapeutics. Search of news anticancer targets is more necessary than ever to tackle this pathology. Heat-Shock Protein 90 (HSP90), a chaperone protein, is implicated in breast cancer pathogenesis, rendering it an appealing target. Looking for alternative approach such as Plant-based compounds and natural HSP90 inhibitors offer promising prospects for innovative therapeutic strategies. This study aims to identify plant-based compounds with anticancer effects on breast cancer models and elucidate their mechanism of action in inhibiting the HSP90 protein. A systematic review was conducted and completed in January 2024 and included in vitro, in vivo, and in silico studies that investigated the effectiveness of plant-based HSP90 inhibitors tested on breast cancer models. Eleven studies were included in the review. Six plants and 24 compounds from six different classes were identified and proved to be effective against HSP90 in breast cancer models. The studied plant extracts showed a dose- and time-dependent decrease in cell viability. Variable IC50 values showed antiproliferative effects, with the plant Tubocapsicum anomalum demonstrating the lowest value. Withanolides was the most studied class. Fennel, Trianthema portulacastrum, and Spatholobus suberectus extracts were shown to inhibit tumor growth and angiogenesis and modulate HSP90 expression as well as its cochaperone interactions in breast cancer mouse models. The identified plant extracts and compounds were proven effective against HSP90 in breast cancer models, and this inhibition showed promising effects on breast cancer biology. Collectively, these results urge the need of further studies to better understand the mechanism of action of HSP90 inhibitors using comparable methods for preclinical observations.

Ovarian cancer is the fifth leading cause of cancer deaths. Chemoresistance, particularly against platinum compounds, contributes to a poor prognosis. Histone deacetylase inhibitors (HDACi) and heat shock protein 90 inhibitors (HSP90i) are known to modulate pathways involved in chemoresistance. This study investigated the effects of HDACi (panobinostat, LMK235) and HSP90i (luminespib, HSP990) on the potency of cisplatin in ovarian cancer cell lines (A2780, CaOV3, OVCAR3 and cisplatin-resistant sub-clones). Preincubation with HDACi increased the cytotoxic potency of HSP90i, whereas preincubation with HSP90i had no effect. Preincubation with HSP90i or HDACi 48h prior to cisplatin enhanced the cisplatin potency significantly in all cell lines via apoptosis induction and affected the expression of apoptosis-relevant genes and proteins. For CaOV3CisR and A2780CisR, a preincubation with HDACi for 48–72 h led to complete reversal of cisplatin resistance. Furthermore, permanent presence of HDACi in sub-cytotoxic concentrations prevented the development of cisplatin resistance in A2780. However, triple combinations of HDACi, HSP90i and cisplatin were not superior to dual combinations. Overall, priming with HDACi sensitizes ovarian cancer cells to treatment with HSP90i or cisplatin and has an influence on the development of cisplatin resistance, both of which may contribute to an improved ovarian cancer treatment.

Cardiovascular disease is the result of complicated pathophysiological processes in the tissues that make up the blood vessels and heart. Heat shock protein 90 (HSP90) can interact with 10% of the proteome and is the most widely studied molecular chaperone in recent years. HSP90 is extensively involved in the regulation of protein folding and intracellular protein stability, making HSP90 a hopeful target for the treatment of multiple cardiovascular diseases. Numerous client proteins of HSP90 have been identified in known cardiac disease pathways, including MAPK signaling, PI3K/AKT (PKB)/mTOR, and TNF-α signaling. Therefore, these pathways can be controlled by regulating HSP90. Among them, the activity of HSP90 can be regulated via numerous inhibitors. In this review, first, we will discuss the function of HSP90 and its role in pathological pathways. In addition, HSP90 plays a significant role in most cardiovascular diseases, including hypertension, pulmonary venous hypertension, atherosclerosis, and heart failure; next we will focus on this part. Finally, we will summarize the currently known HSP90 inhibitors and their potential in the treatment of heart disease.

Heat shock proteins (HSPs) are a large family of chaperones that are involved in protein folding and maturation of a variety of “client” proteins protecting them from degradation, oxidative stress, hypoxia, and thermal stress. Hence, they are significant regulators of cellular proliferation, differentiation and strongly implicated in the molecular orchestration of cancer development and progression as many of their clients are well established oncoproteins in multiple tumor types. Interestingly, tumor cells are more HSP chaperonage-dependent than normal cells for proliferation and survival because the oncoproteins in cancer cells are often misfolded and require augmented chaperonage activity for correction. This led to the development of several inhibitors of HSP90 and other HSPs that have shown promise both preclinically and clinically in the treatment of cancer. In this article, we comprehensively review the roles of some of the important HSPs in cancer, and how targeting them could be efficacious, especially when traditional cancer therapies fail.