Abstract 2453: Inhibition of β-catenin/CBP signaling with E7386 targets epigenetic changes associated with cancer stem cells in head and neck cancer
Authors: Yang Huamei , Kartha Vinay , Alamoud Khalid A. , Federico Anthony , Tilston-Lunel Andrew , Nguyen Bach-Cuc , Owa Takashi , Nomoto Kenichi , Varelas Xaralabos , Monti Stefano , Kukuruzinska Maria A. 
Published: September 2020

Head and neck squamous cell carcinoma (HNSCC) is a pernicious malignancy that arises from populations of cancer stem cells (CSCs). We and others have shown that the Wnt/β-catenin signaling pathway drives CSC gene expression mediated, in part, by epigenetic alterations directed by interactions between nuclear β-catenin and the cAMP-responsive element binding (CREB)-binding protein (CBP). In HNSCC, the β-catenin/CBP complex recruits the histone methyltransferase, MLL1, to drive trimethylation of H3K4me3 to induce an open chromatin structure and expression of CSC genes. Further, β-catenin/CBP signaling is highly correlated with the activity of the paralogous transcriptional regulators YAP and TAZ (YAP/TAZ), which are pro-tumorigenic factors in HNSCC. We reported that a small molecule inhibitor of the β-catenin-CBP interaction, ICG-001, blocks oncogenic phenotypes in cellular, zebrafish, and murine models of HNSCC, concomitant with the reduction of CSC traits. Recently, a novel β-catenin/CBP modulator, E7386, has been shown to be effective against a number of neoplasms in preclinical studies. Here, we compared anti-cancer properties of E7386 with ICG-001 to define its molecular mechanisms and validate the β-catenin/CBP axis as a bona fide therapeutic target in HNSCC.

Anti-HNSCC activity of E7386 was evaluated in four human HNSCC cell lines using genomic, molecular, biochemical and functional approaches, including global ChIP-seq for H3K4me3. The set of transcripts significantly down-regulated by E7386 in HNSCC cells was projected onto a TCGA RNA-seq data (n=318) using ASSIGN, where samples were scored based on the coordinated expression of the gene signature which, in turn, reflected the level of E7386 inhibition per sample. The E7386 inhibition score was then tested for its association with survival by stratifying TCGA patients (n=318) into high- and low-score groups. Results showed that E7386 had highly overlapping activity signatures with ICG-001 (R = 0.997) with ~50 - 100-fold lower EC50. Similar to ICG-001, treatment with E7386 blocked association between β-catenin and CBP with a concomitant reduction in CBP and MLL1 abundance and global H3K4 trimethylation. E7386 repressed an oncogenic gene expression signature regulated by YAP1/TAZ and impeded HNSCC cell proliferation, promoting E-cadherin adhesion and junctional localization of β-catenin. Importantly, E7386 inhibition-associated transcriptional signatures tracked with tumor grade and poor human HNSCC patient survival. In conclusion, inhibiting β-catenin/CBP activity with E7386 represents a novel approach aimed at targeting epigenetically driven changes in the chromatin structure in HNSCC.

Citation Format: Huamei Yang, Vinay Kartha, Khalid A. Alamoud, Anthony Federico, Andrew Tilston-Lunel, Bach-Cuc Nguyen, Takashi Owa, Kenichi Nomoto, Xaralabos Varelas, Stefano Monti, Maria A. Kukuruzinska. Inhibition of β-catenin/CBP signaling with E7386 targets epigenetic changes associated with cancer stem cells in head and neck cancer [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 2453.