ArticleMolecular cancer therapeutics2013
Inhibition of Wee1, AKT, and CDK4 underlies the efficacy of the HSP90 inhibitor XL888 in an in vivo model of NRAS-mutant melanoma.
Article in Molecular cancer therapeutics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
34 citing papers in PubMed, 1 synthesis or guideline pooled it, 54 citations in OpenAlex.
- An update of predictive biomarkers related to WEE1 inhibition in cancer therapy.Journal of cancer research and clinical oncology · 2024Pooled it
- Heat Shock Protein 90: From Molecular Chaperone Function to Therapeutic Targeting in Malignancies.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- HSP90 inhibition potentiates oxidant-based antimelanoma action of novel thioquercetin derivatives by compromising AhR/CYP1A1 pathway.Apoptosis : an international journal on programmed cell death · 2026Article
- Beyond Folding: Expanding the Functional Landscape of Hsp90 Chaperone Machinery in Health and Disease.International journal of molecular sciences · 2025Review
- Combination Strategies with HSP90 Inhibitors in Cancer Therapy: Mechanisms, Challenges, and Future Perspectives.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Multiomic molecular characterization of the response to combination immunotherapy in MSS/pMMR metastatic colorectal cancer.Journal for immunotherapy of cancer · 2024Article
- TargetingJournal of clinical oncology : official journal of the American Society of Clinical Oncology · 2023Article
- Targeting HSP90 as a Novel Therapy for Cancer: Mechanistic Insights and Translational Relevance.Cells · 2022Review
- Targeted Therapy Given after Anti-PD-1 Leads to Prolonged Responses in Mouse Melanoma Models through Sustained Antitumor Immunity.Cancer immunology research · 2021Article
- Novel insights into the pathogenesis and treatment of NRAS mutant melanoma.Expert review of precision medicine and drug development · 2021Article
- Current Perspectives and Novel Strategies ofOncoTargets and therapy · 2021Review
- Review
- Inhibitors of HSP90 in melanoma.Apoptosis : an international journal on programmed cell death · 2020Review
- Old and New Approaches to Target the Hsp90 Chaperone.Current cancer drug targets · 2020Review
- Hsp90 inhibitors enhance the antitumoral effect of osimertinib in parental and osimertinib-resistant non-small cell lung cancer cell lines.Translational lung cancer research · 2019Article
- 17-Aminogeldanamycin selectively diminishes IRE1α-XBP1s pathway activity and cooperatively induces apoptosis with MEK1/2 and BRAFApoptosis : an international journal on programmed cell death · 2019Article
- HDAC8 Regulates a Stress Response Pathway in Melanoma to Mediate Escape from BRAF Inhibitor Therapy.Cancer research · 2019Article
- Ceritinib Enhances the Efficacy of Trametinib inMolecular cancer therapeutics · 2018Article
- Delivery of HSP90 Inhibitor Using Water Soluble Polymeric Conjugates with High Drug Payload.Pharmaceutical research · 2017Article
- Inhibition of HSP90 sensitizes a novel Raf/ERK dual inhibitor CY-9d in triple-negative breast cancer cells.Oncotarget · 2017Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
The HSP90 inhibitor XL888 is effective at reversing BRAF inhibitor resistance in melanoma, including that mediated through acquired NRAS mutations. The present study has investigated the mechanism of action of XL888 in NRAS-mutant melanoma. Treatment of NRAS-mutant melanoma cell lines with XL888 led to an inhibition of growth, G2-M phase cell-cycle arrest, and the inhibition of cell survival in three-dimensional spheroid and colony formation assays. In vitro, HSP90 inhibition led to the degradation of ARAF, CRAF, Wee1, Chk1, and cdc2 and was associated with decreased mitogen-activated protein kinase (MAPK), AKT, mTOR, and c-jun NH2 kinase (JNK) signaling. Apoptosis induction was associated with increased BIM expression and a decrease in the expression of the prosurvival protein Mcl-1. The critical role of increased BIM and decreased Mcl-1 expression in the survival of NRAS-mutant melanoma cell lines was shown through siRNA knockdown and overexpression studies. In an animal xenograft model of NRAS-mutant melanoma, XL888 treatment led to reduced tumor growth and apoptosis induction. Important differences in the pattern of client degradation were noted between the in vivo and in vitro studies. In vivo, XL888 treatment led to degradation of CDK4 and Wee1 and the inhibition of AKT/S6 signaling with little or no effect observed upon ARAF, CRAF, or MAPK. Blockade of Wee1, using either siRNA knockdown or the inhibitor MK1775, was associated with significant levels of growth inhibition and apoptosis induction. Together, these studies have identified Wee1 as a key target of XL888, suggesting novel therapeutic strategies for NRAS-mutant melanoma.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.