The functional GRHL3-filaggrin axis maintains a tumor differentiation potential and influences drug sensitivity

Bai, Y; Zhao, Z; Boath, J; van Denderen, BJ; Darido, C

Author(s): Bai, Y; Zhao, Z; Boath, J; van Denderen, BJ; Darido, C;
Details: Publication Year 2021-08-04,Volume 29,Issue #8,Page 2571-2582
Journal Title: Molecular Therapy
Publication Type: Research article
Abstract: 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.
Keywords: Animals; Biomarkers, Tumor/*genetics; Cell Line, Tumor; Cell Proliferation; DNA-Binding Proteins/*genetics; Filaggrin Proteins/*genetics; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms/*genetics; Humans; Mice; Neoplasm Transplantation; Prognosis; Signal Transduction; Squamous Cell Carcinoma of Head and Neck/*genetics; Transcription Factors/*genetics; Exome Sequencing; Whole Genome Sequencing; Filaggrin; Grhl3; Hnscc; Stat3; biomarkers; c-MYC; differentiation; mTOR; sensitivity; targeted therapy
Department(s): Laboratory Research
PubMed ID: 33775911
Publisher's Version: https://doi.org/10.1016/j.ymthe.2021.03.016
Open Access at Publisher's Site: https://doi.org/10.1016/j.ymthe.2021.03.016
Terms of Use/Rights Notice: Refer to copyright notice on published article.

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