ArticleMolecular cancer therapeutics2015
Wee-1 kinase inhibition overcomes cisplatin resistance associated with high-risk TP53 mutations in head and neck cancer through mitotic arrest followed by senescence.
Article in Molecular cancer therapeutics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 77 papers.
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Who cites it
77 citing papers in PubMed, 109 citations in OpenAlex.
- miR-15b modulates multidrug resistance in human osteosarcoma in vitro and in vivo.Molecular oncology · 2017Trial
- Targeted inhibition of ATR kinase promotes antitumor immunity in HNSCC through enhanced STING activation and T cell function.Translational oncology · 2026Article
- The SMAC-mimetic xevinapant differentially enhances cisplatin and immune checkpoint blockade efficacy in high-risk HPV-positive tumors.Translational oncology · 2026Article
- Targeted suppression of SPP1 inhibits tumor invasion and metastasis in NRF2 hyperactivated cisplatin resistant HNSCC.Journal of translational medicine · 2026Article
- Loss of JAK1 Function Causes G2-M Cell-Cycle Defects Vulnerable to KIF18A Inhibition.Cancer research · 2026Article
- Establishment and characterization of a new immortalized human oral keratinocyte (HOK) cell line harboring various TP53 mutations.Oral oncology · 2026Article
- Therapy-Induced Senescence (TIS) and SASP: The p53-Mediated Interplay in Cancer Progression and Treatment.International journal of molecular sciences · 2025Review
- Discovery of molecularly-informed therapeutic strategies for mature T-cell leukemias and lymphomas.Blood advances · 2025Article
- Enhanced pharmacological activities of AKR1C3-activated prodrug AST-3424 in cancer cells with defective DNA repair.International journal of cancer · 2025Article
- Strategies to Overcome Intrinsic and Acquired Resistance to Chemoradiotherapy in Head and Neck Cancer.Cells · 2024Review
- Results and lessons learnt from the WISTERIA phase I trial combining AZD1775 with cisplatin pre- or post-operatively in head and neck cancer.BJC reports · 2024Article
- Mutant p53 in head and neck squamous cell carcinoma: Molecular mechanism of gain‑of‑function and targeting therapy (Review).Oncology reports · 2023Review
- Review
- Article
- Dysregulation and Epigenetic Reprogramming of NRF2 Signaling Axis Promote Acquisition of Cisplatin Resistance and Metastasis in Head and Neck Squamous Cell Carcinoma.Clinical cancer research : an official journal of the American Association for Cancer Research · 2023Article
- Targeting replication stress in cancer therapy.Nature reviews. Drug discovery · 2023Review
- Clinical Trial Development in TP53-Mutated Locally Advanced and Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma.Journal of the National Cancer Institute · 2022Article
- p53 Modulates Radiosensitivity in Head and Neck Cancers-From Classic to Future Horizons.Diagnostics (Basel, Switzerland) · 2022Review
- DNA Damage Response in Cancer Therapy and Resistance: Challenges and Opportunities.International journal of molecular sciences · 2022Review
- Genome interpretation using in silico predictors of variant impact.Human genetics · 2022Review
17 more citing papers are in PubMed but not listed here.
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Authors and funding
16 authors at 6 institutions in 1 country.
Funding
Abstract
Although cisplatin has played a role in "standard-of-care" multimodality therapy for patients with advanced squamous cell carcinoma of the head and neck (HNSCC), the rate of treatment failure remains particularly high for patients receiving cisplatin whose tumors have mutations in the TP53 gene. We found that cisplatin treatment of HNSCC cells with mutant TP53 leads to arrest of cells in the G2 phase of the cell cycle, leading us to hypothesize that the wee-1 kinase inhibitor MK-1775 would abrogate the cisplatin-induced G2 block and thereby sensitize isogenic HNSCC cells with mutant TP53 or lacking p53 expression to cisplatin. We tested this hypothesis using clonogenic survival assays, flow cytometry, and in vivo tumor growth delay experiments with an orthotopic nude mouse model of oral tongue cancer. We also used a novel TP53 mutation classification scheme to identify which TP53 mutations are associated with limited tumor responses to cisplatin treatment. Clonogenic survival analyses indicate that nanomolar concentration of MK-1775 sensitizes HNSCC cells with high-risk mutant p53 to cisplatin. Consistent with its ability to chemosensitize, MK-1775 abrogated the cisplatin-induced G2 block in p53-defective cells leading to mitotic arrest associated with a senescence-like phenotype. Furthermore, MK-1775 enhanced the efficacy of cisplatin in vivo in tumors harboring TP53 mutations. These results indicate that HNSCC cells expressing high-risk p53 mutations are significantly sensitized to cisplatin therapy by the selective wee-1 kinase inhibitor, supporting the clinical evaluation of MK-1775 in combination with cisplatin for the treatment of patients with TP53 mutant HNSCC.
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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.