Targeting oncogenic β-catenin/CBP activity for the treatment of head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) presents primarily as oral squamous cell carcinoma (OSCC), an aggressive malignancy characterized by heterogeneity, locoregional metastases and resistance to existing treatments. Although a number of molecular alterations associated with OSCC have been identified, they have had limited impact on clinical management. A frequent feature of OSCC is the inappropriate activation of nuclear β-catenin. Here, we provide a comprehensive characterization of the effects of blocking the interaction between nuclear β-catenin and the cAMP-responsive element binding (CREB)-binding protein (CBP) using the small molecule inhibitor ICG-001. We demonstrate that ICG-001 inhibits cell proliferation and aggressive OSCC cell phenotypes in cellular, zebrafish and murine models, and that its inhibition-associated transcriptional signature tracks with advanced tumor grade and poor survival in human patients. Our results suggest that targeting the β-catenin/CBP interaction in the nucleus represents a new and effective therapy for OSCC. Microarray gene expression profiling pertaining to ICG-001 or DMSO (control) treatment in HSC-3 and CAL27 cells, and siCTNNB1 or scrambled siRNA control in HSC-3 cells ; n=3 per treatment group, per cell line). Note: the preprocessed data were generated from two normalizations: 1) samples GSM2522361-GSM2522372, and 2) samples GSM2522373-GSM2522378, plus six other arrays that are not included in this Series. The preprocessed data for samples GSM2522373-GSM2522378 therefore cannot be reproduced entirely from this Series alone.