{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T11:55:36Z","timestamp":1782561336680,"version":"3.54.5"},"reference-count":45,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,4,16]],"date-time":"2025-04-16T00:00:00Z","timestamp":1744761600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fight Kids Cancer Funding Programme","award":["BT4ChildLC"],"award-info":[{"award-number":["BT4ChildLC"]}]},{"name":"Bettina Br\u00e4u Foundation Munich","award":["BT4ChildLC"],"award-info":[{"award-number":["BT4ChildLC"]}]},{"name":"G\u00e4nsebl\u00fcmchen Association Voerde","award":["BT4ChildLC"],"award-info":[{"award-number":["BT4ChildLC"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Hepatoblastoma, the most common malignant liver tumor in pediatric patients, is characterized by a remarkably low mutation rate, thereby impeding targeted therapies. Current treatment regimens rely on conventional cytotoxic agents that often cause severe adverse effects, necessitating the search for novel, less toxic therapeutic approaches. Methods: In this study, we explored the anti-tumor potential of heat shock protein 90 (HSP90) inhibitors using a unique collection of hepatoblastoma in vitro models. Results: Among the five tested inhibitors, we identified ganetespib as the most effective, significantly suppressing tumor cell growth while sparing healthy, non-tumor cells. Ganetespib treatment at low nanomolar concentrations markedly reduced cell proliferation, impaired long-term survival, and inhibited three-dimensional spheroid growth, ultimately leading to the induction of apoptosis. Mechanistically, ganetespib downregulated the expression of the HSP90 client protein cyclin-dependent kinase 1, a key cell cycle regulator controlling G2\/M phase transition, which is heavily upregulated in hepatoblastoma. This disruption consequently resulted in cell cycle arrest, further contributing to its anti-tumor effects. Conclusions: HSP90 inhibition by ganetespib demonstrates significant potential as a novel therapeutic strategy for hepatoblastoma, offering a potential alternative to current cytotoxic treatments with fewer adverse effects.<\/jats:p>","DOI":"10.3390\/cancers17081341","type":"journal-article","created":{"date-parts":[[2025,4,16]],"date-time":"2025-04-16T06:12:06Z","timestamp":1744783926000},"page":"1341","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Targeting HSP90 with Ganetespib to Induce CDK1 Degradation and Promote Cell Death in Hepatoblastoma"],"prefix":"10.3390","volume":"17","author":[{"given":"Lea Amelie","family":"Jung","sequence":"first","affiliation":[{"name":"Department of Pediatric Surgery, Dr. von Hauner Children\u2019s Hospital, LMU University Hospital, 80337 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-3478-1136","authenticated-orcid":false,"given":"Salih","family":"Demir","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Dr. von Hauner Children\u2019s Hospital, LMU University Hospital, 80337 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alina","family":"Hotes","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Dr. von Hauner Children\u2019s Hospital, LMU University Hospital, 80337 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9179-5037","authenticated-orcid":false,"given":"Eiso","family":"Hiyama","sequence":"additional","affiliation":[{"name":"Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima 739-0046, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2515-1054","authenticated-orcid":false,"given":"Tomoro","family":"Hishiki","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8677, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8974-6551","authenticated-orcid":false,"given":"Emilie","family":"Indersie","sequence":"additional","affiliation":[{"name":"XenTech, 91000 Evry, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Branchereau","sequence":"additional","affiliation":[{"name":"Bic\u00eatre Hospital, AP-HP Paris Saclay University, 94270 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4725-5970","authenticated-orcid":false,"given":"Stefano","family":"Cairo","sequence":"additional","affiliation":[{"name":"Champions Oncology, Inc., Rockville, MD 20850, USA"},{"name":"Pediatric Research Institute (IRP), 35127 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8581-2803","authenticated-orcid":false,"given":"Roland","family":"Kappler","sequence":"additional","affiliation":[{"name":"Department of Pediatric Surgery, Dr. von Hauner Children\u2019s Hospital, LMU University Hospital, 80337 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1002\/pbc.24215","article-title":"The epidemiology of hepatoblastoma","volume":"59","author":"Spector","year":"2012","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"555","DOI":"10.21037\/atm.2019.09.76","article-title":"Survival and analysis of prognostic factors for hepatoblastoma: Based on SEER database","volume":"7","author":"Feng","year":"2019","journal-title":"Ann. Transl. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1662","DOI":"10.1056\/NEJMoa0810613","article-title":"Cisplatin versus cisplatin plus doxorubicin for standard-risk hepatoblastoma","volume":"361","author":"Perilongo","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1016\/S1470-2045(13)70272-9","article-title":"Dose-dense cisplatin-based chemotherapy and surgery for children with high-risk hepatoblastoma (SIOPEL-4): A prospective, single-arm, feasibility study","volume":"14","author":"Zsiros","year":"2013","journal-title":"Lancet Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3267","DOI":"10.2174\/092986709788803312","article-title":"Doxorubicin: The good, the bad and the ugly effect","volume":"16","author":"Carvalho","year":"2009","journal-title":"Curr. Med. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.2165\/11316640-000000000-00000","article-title":"Cisplatin overdose: Toxicities and management","volume":"32","author":"Tsang","year":"2009","journal-title":"Drug Saf."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1016\/j.jhep.2014.08.009","article-title":"The genomic landscape of hepatoblastoma and their progenies with HCC-like features","volume":"61","author":"Trippel","year":"2014","journal-title":"J. Hepatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2524","DOI":"10.1158\/2159-8290.CD-20-1809","article-title":"Integrated Genomic Analysis Identifies Driver Genes and Cisplatin-Resistant Progenitor Phenotype in Pediatric Liver Cancer","volume":"11","author":"Hirsch","year":"2021","journal-title":"Cancer Discov."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"5423","DOI":"10.1038\/s41467-021-25430-9","article-title":"Genetic and epigenetic basis of hepatoblastoma diversity","volume":"12","author":"Nagae","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_10","first-page":"269","article-title":"Childhood hepatoblastomas frequently carry a mutated degradation targeting box of the beta-catenin gene","volume":"59","author":"Koch","year":"1999","journal-title":"Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1136\/gut.39.6.867","article-title":"Hepatoblastoma and APC gene mutation in familial adenomatous polyposis","volume":"39","author":"Giardiello","year":"1996","journal-title":"Gut"},{"key":"ref_12","first-page":"w20129","article-title":"Targeting the Wnt signalling pathway in cancer: Prospects and perils","volume":"149","author":"Shaw","year":"2019","journal-title":"Swiss Med. Wkly."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.ejca.2020.09.026","article-title":"A combined clinical and biological risk classification improves prediction of outcome in hepatoblastoma patients","volume":"141","author":"Cairo","year":"2020","journal-title":"Eur. J. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1038\/nrm.2017.20","article-title":"The HSP90 chaperone machinery","volume":"18","author":"Schopf","year":"2017","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1158\/2159-8290.CD-21-1059","article-title":"Hallmarks of Cancer: New Dimensions","volume":"12","author":"Hanahan","year":"2022","journal-title":"Cancer Discov."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1038\/nrc1716","article-title":"HSP90 and the chaperoning of cancer","volume":"5","author":"Whitesell","year":"2005","journal-title":"Nat. Rev. Cancer"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1310","DOI":"10.1002\/hep.20962","article-title":"Role of HSP90, CDC37, and CRM1 as modulators of P16(INK4A) activity in rat liver carcinogenesis and human liver cancer","volume":"42","author":"Pascale","year":"2005","journal-title":"Hepatology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2072","DOI":"10.3748\/wjg.v11.i14.2072","article-title":"Expression of heat shock proteins (HSP27, HSP60, HSP70, HSP90, GRP78, GRP94) in hepatitis B virus-related hepatocellular carcinomas and dysplastic nodules","volume":"11","author":"Lim","year":"2005","journal-title":"World J. Gastroenterol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.ajpath.2022.10.006","article-title":"Inhibition of Heat Shock Factor 1 Signaling Decreases Hepatoblastoma Growth via Induction of Apoptosis","volume":"193","author":"Hurley","year":"2023","journal-title":"Am. J. Pathol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3540","DOI":"10.1158\/1538-7445.AM2023-3540","article-title":"Reduction in cell viability of hepatoblastoma cells following inhibtion of Hsp90","volume":"83","author":"Kissoondoyal","year":"2023","journal-title":"Cancer Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5132","DOI":"10.1158\/1078-0432.CCR-11-0072","article-title":"HSP90 inhibition is effective in breast cancer: A phase II trial of tanespimycin (17-AAG) plus trastuzumab in patients with HER2-positive metastatic breast cancer progressing on trastuzumab","volume":"17","author":"Modi","year":"2011","journal-title":"Clin. Cancer Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1007\/s40265-022-01764-6","article-title":"Pimitespib: First Approval","volume":"82","author":"Hoy","year":"2022","journal-title":"Drugs"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1007\/s10637-014-0164-8","article-title":"A phase I and pharmacokinetic study of ganetespib (STA-9090) in advanced hepatocellular carcinoma","volume":"33","author":"Goyal","year":"2015","journal-title":"Investig. New Drugs"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1186\/s13046-024-03221-6","article-title":"Drug prioritization identifies panobinostat as a tailored treatment element for patients with metastatic hepatoblastoma","volume":"43","author":"Demir","year":"2024","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1002\/hep.22649","article-title":"Blocking the hedgehog pathway inhibits hepatoblastoma growth","volume":"49","author":"Gruner","year":"2009","journal-title":"Hepatology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e45","DOI":"10.1093\/nar\/29.9.e45","article-title":"A new mathematical model for relative quantification in real-time RT-PCR","volume":"29","author":"Pfaffl","year":"2001","journal-title":"Nucleic Acids Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e0378","DOI":"10.1097\/HC9.0000000000000378","article-title":"Targeting G9a\/DNMT1 methyltransferase activity impedes IGF2-mediated survival in hepatoblastoma","volume":"8","author":"Demir","year":"2024","journal-title":"Hepatol. Commun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2584","DOI":"10.1200\/JCO.2009.22.4857","article-title":"Successful treatment of childhood high-risk hepatoblastoma with dose-intensive multiagent chemotherapy and surgery: Final results of the SIOPEL-3HR study","volume":"28","author":"Zsiros","year":"2010","journal-title":"J. Clin. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1530","DOI":"10.4161\/cc.3.12.1277","article-title":"Hsp90 activation and cell cycle regulation","volume":"3","author":"Burrows","year":"2004","journal-title":"Cell Cycle"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Echeverria, P.C., Bernthaler, A., Dupuis, P., Mayer, B., and Picard, D. (2011). An interaction network predicted from public data as a discovery tool: Application to the Hsp90 molecular chaperone machine. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0026044"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"6403","DOI":"10.18632\/oncotarget.27237","article-title":"Volasertib preclinical activity in high-risk hepatoblastoma","volume":"10","author":"Kats","year":"2019","journal-title":"Oncotarget"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1002\/hon.3110","article-title":"Heat shock protein 90 inhibitors induce cell differentiation via the ubiquitin-dependent aurora kinase A degradation in a MPLW515L mouse model of primary myelofibrosis","volume":"41","author":"Wang","year":"2023","journal-title":"Hematol. Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1340","DOI":"10.1038\/s41591-023-02339-y","article-title":"A joint international consensus statement for measuring quality of survival for patients with childhood cancer","volume":"29","author":"Hudson","year":"2023","journal-title":"Nat. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/j.cstres.2024.05.005","article-title":"An update on the status of HSP90 inhibitors in cancer clinical trials","volume":"29","author":"Rastogi","year":"2024","journal-title":"Cell Stress Chaperones"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Saber, S., Hasan, A.M., Mohammed, O.A., Saleh, L.A., Hashish, A.A., Alamri, M.M.S., Al-Ameer, A.Y., Alfaifi, J., Senbel, A., and Aboregela, A.M. (2023). Ganetespib (STA-9090) augments sorafenib efficacy via necroptosis induction in hepatocellular carcinoma: Implications from preclinical data for a novel therapeutic approach. Biomed. Pharmacother., 164.","DOI":"10.1016\/j.biopha.2023.114918"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Goldman, J.W., Raju, R.N., Gordon, G.A., El-Hariry, I., Teofilivici, F., Vukovic, V.M., Bradley, R., Karol, M.D., Chen, Y., and Guo, W. (2013). A first in human, safety, pharmacokinetics, and clinical activity phase I study of once weekly administration of the Hsp90 inhibitor ganetespib (STA-9090) in patients with solid malignancies. BMC Cancer, 13.","DOI":"10.1186\/1471-2407-13-152"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"M111.016675","DOI":"10.1074\/mcp.M111.016675","article-title":"Systematic identification of the HSP90 candidate regulated proteome","volume":"11","author":"Wu","year":"2012","journal-title":"Mol. Cell Proteom."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1196\/annals.1391.012","article-title":"Drugging the cancer chaperone HSP90: Combinatorial therapeutic exploitation of oncogene addiction and tumor stress","volume":"1113","author":"Workman","year":"2007","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Bhattacharyya, N., Gupta, S., Sharma, S., Soni, A., Bagabir, S.A., Bhattacharyya, M., Mukherjee, A., Almalki, A.H., Alkhanani, M.F., and Haque, S. (2022). CDK1 and HSP90AA1 Appear as the Novel Regulatory Genes in Non-Small Cell Lung Cancer: A Bioinformatics Approach. J. Pers. Med., 12.","DOI":"10.3390\/jpm12030393"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"8115474","DOI":"10.1155\/2022\/8115474","article-title":"Systematic Pan-Cancer Analysis Identifies CDK1 as an Immunological and Prognostic Biomarker","volume":"2022","author":"Yang","year":"2022","journal-title":"J. Oncol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"300060519897508","DOI":"10.1177\/0300060519897508","article-title":"CDK1 serves as a potential prognostic biomarker and target for lung cancer","volume":"48","author":"Li","year":"2020","journal-title":"J. Int. Med. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.bbrc.2021.02.117","article-title":"CDK1 inhibitor controls G2\/M phase transition and reverses DNA damage sensitivity","volume":"550","author":"Sunada","year":"2021","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Liu, H., Lu, Z., Shi, X., Liu, L., Zhang, P., Golemis, E.A., and Tu, Z. (2021). HSP90 inhibition downregulates DNA replication and repair genes via E2F1 repression. J. Biol. Chem., 297.","DOI":"10.1016\/j.jbc.2021.100996"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1186\/s12935-019-0999-3","article-title":"PADI3 plays an antitumor role via the Hsp90\/CKS1 pathway in colon cancer","volume":"19","author":"Chai","year":"2019","journal-title":"Cancer Cell Int."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Huang, Z., Zhou, X., He, Y., Ke, X., Wen, Y., Zou, F., and Chen, X. (2016). Hyperthermia enhances 17-DMAG efficacy in hepatocellular carcinoma cells with aggravated DNA damage and impaired G2\/M transition. Sci. Rep., 6.","DOI":"10.1038\/srep38072"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/8\/1341\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:15:29Z","timestamp":1760030129000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/8\/1341"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,16]]},"references-count":45,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["cancers17081341"],"URL":"https:\/\/doi.org\/10.3390\/cancers17081341","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,16]]}}}