Description
Presentation Blocks: 03-23-2018 - Friday - 03:45 PM - 05:00 PM

Title: Inhibition of EGFR by Targeting β-catenin/CBP Signaling in Oral Cancer

Authors:

Khalid Alamoud (Presenter)
Boston University

Kevin Chandler, Boston University, School of Medicine
Vinay Kartha, Boston University
Stefano Monti, Boston University
Catherine Costello, Boston University, School of Medicine
Maria Kukuruzinska, Boston University

Abstract:

Objectives: Head and neck cancer presents primarily as head and neck squamous cell carcinoma (HNSCC) with the majority of cases arising in the oral cavity as oral squamous cell carcinoma (OSCC). One feature underlying OSCC pathogenesis is upregulation of the epidermal growth factor receptor (EGFR) activity, for which a targeted therapy with cetuximab, a monoclonal antibody to EGFR, is available. However, cetuximab has a modest clinical response rate of less than 20%. We have shown that increased oncogenic signaling of β-catenin is associated with pathobiology of OSCC, and that inhibition of β-catenin’s interaction with CREB-binding protein (CBP) in the nucleus with a small molecule inhibitor ICG-001 restores epithelial phenotype in cellular models and inhibits invasive tumor growth in nude and immune competent mouse models. Remarkably, we also found that ICG-001 dramatically inhibited EGFR protein levels without impacting its transcript abundance. Among genes inhibited by ICG-001 were proliferation-, stemness-, and survival-inducing genes, as well as key regulatory genes in the protein N-glycosylation pathway. As EGFR requires N-glycosylation for activity, we hypothesized that ICG-001 impacted its N-glycosylation status.

Methods: OSCC cell lines including indolent CAL27 and invasive HSC-3 cells were treated with either DMSO control or ICG-001 and EGFR was immunoprecipitated from total cell lysates. We employed a nano-liquid chromatography tandem mass spectrometry approach to assess EGFR site-specific glycosylation in control and treated cells. In parallel, gene set enrichment analyses were carried out to determine correlation between ICG-001 and EGFR inhibition signatures in The Cancer Genome Atlas (TCGA).

Results: EGFR isolated from ICG-001-treated cells displayed increased modification with sialic acid and fucose, shown to suppress its dimerization and activation. Furthermore, ICG-001 inhibition positively correlated with EGFR inhibition in TCGA.

Conclusions: Inhibition of β-catenin-CBP interaction with ICG-001 represents a powerful approach to intercept OSCC by targeting multiple pro-tumorigenic activities on transcriptional and posttranslational levels.

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