ArticleBMC cancer2017
HSP90 inhibition sensitizes head and neck cancer to platin-based chemoradiotherapy by modulation of the DNA damage response resulting in chromosomal fragmentation.
Article in BMC cancer, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 39 citations in OpenAlex.
- High-throughput drug screening identifies EGFR/MAPK pathway targeting sensitivities in organoid models of ovarian carcinosarcoma.Journal of experimental & clinical cancer research : CR · 2026Article
- Review
- Strategies for Anticancer Treatment in p53-Mutated Head and Neck Squamous Cell Carcinoma.Biomedicines · 2025Article
- Molecular pathway of anticancer effect of next-generation HSP90 inhibitors XL-888 and Debio0932 in neuroblastoma cell line.Medical oncology (Northwood, London, England) · 2024Article
- Review
- Therapeutic Advances and Challenges for the Management of HPV-Associated Oropharyngeal Cancer.International journal of molecular sciences · 2024Review
- New insights into RAS in head and neck cancer.Biochimica et biophysica acta. Reviews on cancer · 2023Review
- Genomic landscape of pleural and peritoneal mesothelioma tumours.British journal of cancer · 2022Article
- Evaluation of the Heat Shock Protein 90 Inhibitor Ganetespib as a Sensitizer to Hyperthermia-Based Cancer Treatments.Cancers · 2022Article
- Temozolomide increases heat shock proteins in extracellular vesicles released from glioblastoma cells.Molecular biology reports · 2022Article
- Heat-activated nanomedicine formulation improves the anticancer potential of the HSP90 inhibitor luminespib in vitro.Scientific reports · 2021Article
- Targeting Stress-Response Pathways and Therapeutic Resistance in Head and Neck Cancer.Frontiers in oral health · 2021Review
- Alterations of DNA damage repair in cancer: from mechanisms to applications.Annals of translational medicine · 2020Review
- Inflammatory microenvironment remodelling by tumour cells after radiotherapy.Nature reviews. Cancer · 2020Review
- Heat Shock Proteins: Agents of Cancer Development and Therapeutic Targets in Anti-Cancer Therapy.Cells · 2019Review
- Cancer drug resistance: rationale for drug delivery systems and targeted inhibition of HSP90 family proteins.Cancer drug resistance (Alhambra, Calif.) · 2019Review
- Mutant p53 as a guardian of the cancer cell.Cell death and differentiation · 2019Review
- CIP2A depletion potentiates the chemosensitivity of cisplatin by inducing increased apoptosis in bladder cancer cells.Oncology reports · 2018Article
- Heat shock proteins and DNA repair mechanisms: an updated overview.Cell stress & chaperones · 2018Review
- The stiff RhoAd from mevalonate to mutant p53.Cell death and differentiation · 2018Review
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 1 country.
Funding
Abstract
backgroundConcurrent cisplatin radiotherapy (CCRT) is a current standard-of-care for locally advanced head and neck squamous cell carcinoma (HNSCC). However, CCRT is frequently ineffective in patients with advanced disease. It has previously been shown that HSP90 inhibitors act as radiosensitizers, but these studies have not focused on CCRT in HNSCC. Here, we evaluated the HSP90 inhibitor, AUY922, combined with CCRT.
methodsThe ability of AUY922 to sensitize to CCRT was assessed in p53 mutant head and neck cell lines by clonogenic assay. Modulation of the CCRT induced DNA damage response (DDR) by AUY922 was characterized by confocal image analysis of RAD51, BRCA1, 53BP1, ATM and mutant p53 signaling. The role of FANCA depletion by AUY922 was examined using shRNA. Cell cycle checkpoint abrogation and chromosomal fragmentation was assessed by western blot, FACS and confocal. The role of ATM was also assessed by shRNA. AUY922 in combination with CCRT was assessed in vivo.
resultsThe combination of AUY922 with cisplatin, radiation and CCRT was found to be synergistic in p53 mutant HNSCC. AUY922 leads to significant alterations to the DDR induced by CCRT. This comprises inhibition of homologous recombination through decreased RAD51 and pS1524 BRCA1 with a corresponding increase in 53BP1 foci, activation of ATM and signaling into mutant p53. A shift to more error prone repair combined with a loss of checkpoint function leads to fragmentation of chromosomal material. The degree of disruption to DDR signalling correlated to chromosomal fragmentation and loss of clonogenicity. ATM shRNA indicated a possible rationale for the combination of AUY922 and CCRT in cells lacking ATM function.
conclusionsThis study supports future clinical studies combining AUY922 and CCRT in p53 mutant HNSCC. Modulation of the DDR and chromosomal fragmentation are likely to be analytical points of interest in such trials.
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