Abstract 6566: Defining the effects of inhibiting the beta-catenin-CBP signaling axis with the small molecule E7386 by integrative analysis of omics data

Abstract

Abstract Head and neck squamous cell carcinoma (HNSCC) is associated with high morbidity, poor survival rates, and limited treatment options. We previously reported that aberrant activation of nuclear β-catenin/cAMP-responsive element binding (CREB)-binding protein (CBP) signaling in primary HNSCC tumors was associated with progression to advanced disease and poor patient survival. Further, inhibition of β-catenin-CBP interaction with the first-generation inhibitor, ICG-001, greatly attenuated aggressive properties of HNSCC cells and tumor growth and metastases in murine and zebrafish models. Our recent findings show that a novel β-catenin/CBP modulator, E7386, displays an activity profile that closely overlaps with that of ICG-001, but exhibits ~50-100-fold lower EC50 values. In this study, we used a novel method for gene regulatory network (GRN) reconstruction which analyzes publicly available high-throughput transcriptomics data from HNSCC to further elucidate the mechanisms of β-catenin-CBP inhibition by E7386. A Bayesian framework was used to reconstruct high-dimensional GRNs using constraint-based and shared structure learning from bulk RNA-seq data from TCGA. HNSCC patients were grouped into two subtypes, based on their “high” vs. “low” response to E7386 inhibition as predicted by the activation - or enrichment by Gene Set Variation Analysis (GSVA) - of the transcriptional signature we derived. GRNs for the two subtypes were built, and their comparison highlighted new interactions in the “high” responders network between the β-catenin/CBP network and genes associated with histone modifications (ASH1L) and amino acid metabolism (MTR) concomitant with loss of interactions with regulators of cell cycle (ERCC6L) and protein secretion (SCAMP1) identified in the “low” responders network. Additionally, Kaplan-Meier survival plots showed that HNSCC patients with high activation of the E7386 signature had a significantly lower probability of survival. These results suggest that our GRN-based approach represents an important novel tool for assessing changes in regulatory network interactions in HNSCC and cancer. Citation Format: Anthony Federico, Takashi Owa, Kenichi Nomoto, Xaralabos Varelas, Maria Kukuruzinksa, Stefano Monti. Defining the effects of inhibiting the beta-catenin-CBP signaling axis with the small molecule E7386 by integrative analysis of omics data [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6566.