Functional and genomic analyses reveal therapeutic potential of targeting β-catenin/CBP activity in head and neck cancer

• DOI: 10.1186/s13073-018-0569-7
• Publication Date: 2018-07-20T09:36:07Z
• Authors: Vinay K. Kartha; Khalid A. Abalkhail; Khikmet Sadykov; Bach-Cuc Nguyen; Fabrice Laroche; Hui Feng; Jina Lee; Sara I. Pai; Xaralabos Varelas; Ann Marie Egloff; Jennifer E. Snyde...; Anna C. Belkina; Manish V. Bais; Stefano Monti; Maria A. Kukuruzi...
• Keywords: Human genetics

Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy characterized by tumor heterogeneity, locoregional metastases, resistance to existing treatments. Although a number of genomic molecular alterations associated with HNSCC have been identified, they had limited impact on the clinical management this disease. To date, few targeted therapies are available for HNSCC, only small fraction patients benefited from these A frequent feature inappropriate activation β-catenin that has implicated in survival maintenance expansion stem cell-like populations, thought be underlying cause recurrence treatment. However, therapeutic value targeting activity not explored. We utilized combination computational experimental profiling approaches examine effects blocking interaction between cAMP-responsive element binding (CREB)-binding protein (CBP) using molecule inhibitor ICG-001. generated annotated vitro treatment gene expression signatures cells, derived human oral carcinomas (OSCCs), microarrays. validated anti-tumorigenic ICG-001 vivo SCC-derived xenografts murine models, as well embryonic zebrafish-based screens sorted subpopulations. Additionally, ICG-001-inhibition were overlaid RNA-sequencing data The Cancer Genome Atlas (TCGA) OSCCs evaluate its association progression prognosis. inhibited proliferation growth cellular respectively, while promoting intercellular adhesion loss invasive phenotypes. Furthermore, preferentially ability subpopulations stem-like cells establish metastatic tumors zebrafish. Significantly, interrogation inhibition-associated signature TCGA OSCC cohort indicated β-catenin/CBP transcriptional tracked status, advanced grade, poor overall patient survival. Collectively, our results identify novel target anti-HNSCC therapy provide evidence derivatives enhanced inhibitory may serve effective strategy interfere features HNSCC.