ZFIN ID: ZDB-PUB-180722-14
Functional and genomic analyses reveal therapeutic potential of targeting β-catenin/CBP activity in head and neck cancer
Kartha, V.K., Alamoud, K.A., Sadykov, K., Nguyen, B.C., Laroche, F., Feng, H., Lee, J., Pai, S.I., Varelas, X., Egloff, A.M., Snyder-Cappione, J.E., Belkina, A.C., Bais, M.V., Monti, S., Kukuruzinska, M.A.
Date: 2018
Source: Genome Medicine   10: 54 (Journal)
Registered Authors: Feng, Hui
Keywords: Aggressive tumor cells, HNSCC, ICG-001, TCGA, β-Catenin/CBP transcriptional activity
MeSH Terms:
  • Animals
  • Bridged Bicyclo Compounds, Heterocyclic/pharmacology
  • Bridged Bicyclo Compounds, Heterocyclic/therapeutic use
  • Carcinoma, Squamous Cell/drug therapy
  • Carcinoma, Squamous Cell/genetics
  • Carcinoma, Squamous Cell/pathology
  • Cell Adhesion/genetics
  • Cell Line, Tumor
  • Cell Proliferation/drug effects
  • Cell Survival/genetics
  • Disease Progression
  • Epithelial Cells/drug effects
  • Epithelial Cells/pathology
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic/drug effects
  • Genomics*
  • Head and Neck Neoplasms/drug therapy*
  • Head and Neck Neoplasms/genetics*
  • Head and Neck Neoplasms/pathology
  • Humans
  • Mice, Inbred C57BL
  • Mice, Nude
  • Molecular Targeted Therapy*
  • Mouth Neoplasms/drug therapy
  • Mouth Neoplasms/genetics
  • Mouth Neoplasms/pathology
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Neoplastic Stem Cells/metabolism
  • Neoplastic Stem Cells/pathology
  • Peptide Fragments/metabolism*
  • Phenotype
  • Pyrimidinones/pharmacology
  • Pyrimidinones/therapeutic use
  • Sialoglycoproteins/metabolism*
  • Survival Analysis
  • Wnt Signaling Pathway/genetics
  • Zebrafish/embryology
  • beta Catenin/metabolism*
PubMed: 30029671 Full text @ Genome Med.
FIGURES
ABSTRACT
Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy characterized by tumor heterogeneity, locoregional metastases, and resistance to existing treatments. Although a number of genomic and molecular alterations associated with HNSCC have been identified, they have had limited impact on the clinical management of this disease. To date, few targeted therapies are available for HNSCC, and only a small fraction of patients have benefited from these treatments. A frequent feature of HNSCC is the inappropriate activation of β-catenin that has been implicated in cell survival and in the maintenance and expansion of stem cell-like populations, thought to be the underlying cause of tumor recurrence and resistance to treatment. However, the therapeutic value of targeting β-catenin activity in HNSCC has not been explored.
We utilized a combination of computational and experimental profiling approaches to examine the effects of blocking the interaction between β-catenin and cAMP-responsive element binding (CREB)-binding protein (CBP) using the small molecule inhibitor ICG-001. We generated and annotated in vitro treatment gene expression signatures of HNSCC cells, derived from human oral squamous cell carcinomas (OSCCs), using microarrays. We validated the anti-tumorigenic activity of ICG-001 in vivo using SCC-derived tumor xenografts in murine models, as well as embryonic zebrafish-based screens of sorted stem cell-like subpopulations. Additionally, ICG-001-inhibition signatures were overlaid with RNA-sequencing data from The Cancer Genome Atlas (TCGA) for human OSCCs to evaluate its association with tumor progression and prognosis.
ICG-001 inhibited HNSCC cell proliferation and tumor growth in cellular and murine models, respectively, while promoting intercellular adhesion and loss of invasive phenotypes. Furthermore, ICG-001 preferentially targeted the ability of subpopulations of stem-like cells to establish metastatic tumors in zebrafish. Significantly, interrogation of the ICG-001 inhibition-associated gene expression signature in the TCGA OSCC human cohort indicated that the targeted β-catenin/CBP transcriptional activity tracked with tumor status, advanced tumor grade, and poor overall patient survival.
Collectively, our results identify β-catenin/CBP interaction as a novel target for anti-HNSCC therapy and provide evidence that derivatives of ICG-001 with enhanced inhibitory activity may serve as an effective strategy to interfere with aggressive features of HNSCC.
ADDITIONAL INFORMATION