The functional GRHL3-filaggrin axis maintains a tumor differentiation potential and influences drug sensitivity
| Autor: | Charbel Darido, Jarryd Boath, Bryce J. van Denderen, Yuchen Bai, Zixuan Zhao |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
medicine.medical_treatment
Filaggrin Proteins Targeted therapy Mice 03 medical and health sciences 0302 clinical medicine Cell Line Tumor Exome Sequencing Drug Discovery Biomarkers Tumor Genetics medicine Animals Humans STAT3 Molecular Biology PI3K/AKT/mTOR pathway Cell Proliferation 030304 developmental biology Pharmacology 0303 health sciences Whole Genome Sequencing biology Squamous Cell Carcinoma of Head and Neck business.industry Cancer Prognosis medicine.disease Head and neck squamous-cell carcinoma DNA-Binding Proteins Gene Expression Regulation Neoplastic Head and Neck Neoplasms 030220 oncology & carcinogenesis Cancer cell biology.protein Cancer research Molecular Medicine Biomarker (medicine) business Neoplasm Transplantation Signal Transduction Transcription Factors Filaggrin |
| Zdroj: | Molecular Therapy. 29:2571-2582 |
| ISSN: | 1525-0016 |
| DOI: | 10.1016/j.ymthe.2021.03.016 |
| Popis: | Current therapies for treating heterogeneous cancers such as head and neck squamous cell carcinoma (HNSCC) are non-selective and are administered independent of response biomarkers. Therapy resistance subsequently emerges, resulting in increased cellular proliferation that is associated with loss of differentiation. Whether a cancer cell differentiation potential can dictate therapy responsiveness is still currently unknown. A multi-omic approach integrating whole-genome and whole-transcriptome sequencing with drug sensitivity was employed in a HNSCC mouse model, primary patients' data, and human cell lines to assess the potential of functional differentiation in predicting therapy response. Interestingly, a subset of HNSCC with effective GRHL3-dependent differentiation was the most sensitive to inhibitors of PI3K/mTOR, c-Myc, and STAT3 signaling. Furthermore, we identified the GRHL3-differentiation target gene Filaggrin (FLG) as a response biomarker and more importantly, stratified HNSCC subsets as treatment resistant based on their FLG mutational profile. The loss of FLG in sensitive HNSCC resulted in a dramatic resistance to targeted therapies while the GRHL3-FLG signature predicted a favorable patient prognosis. This study provides evidence for a functional GRHL3-FLG tumor-specific differentiation axis that regulates targeted therapy response in HNSCC and establishes a rationale for clinical investigation of differentiation-paired targeted therapy in heterogeneous cancers. |
| Databáze: | OpenAIRE |
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