Abstract A26: Genomic and epigenomic analysis reveal a distinct and targetable transcriptional signature of HNSCC subtypes

Abstract

Abstract Head and neck squamous cell carcinoma (HNSCC) is a complex disease of significant morbidity and mortality with poor survival rates that have persisted despite advances in therapy. The lack of improved outcome can be attributed, in part, to a gap in the understanding of the drivers of the disease and the paucity of novel targeted treatments. Although recent studies into the genomic landscapes of HNSCC have highlighted a striking mutational heterogeneity, the identification of pervasive and broadly actionable driver mutations and/or other genetic alterations remains elusive. In parallel with this genetic diversity, the heterogeneity of HNSCC is also manifested in distinct gene expression-defined subtypes. This raises the possibility that these heterogeneous gene expression programs are shaped by regulatory networks that are closely interwoven with an intrinsic and heritable epigenetic state. We thus hypothesize that there exist key oncogenic transcriptional regulators that confer subtype specificity and dependency and that these factors are linked with and potentially configure the epigenetic states of HNSCC. We have examined the distributions of histone modification marks by ChIP-Seq and steady-state transcriptomes by RNA-Seq across several cell lines that represent the subtypes of HNSCC. Interestingly, our molecular profiling demonstrated differential enrichment patterns of enhancer-associated H3K27Ac signals that recapitulate the segregation of cell lines based on subtype-specific differential gene expression profiles. We have further probed the enhancer landscape to identify cis-regulatory networks (CRM) specific to HPV-ve subtypes (basal and mesenchymal) and the HPV+ve (atypical) subtype. Embedded within the regulatory domains of the CRMs, we find the DNA-binding motifs of transcription factor (TF) families, including AP-1, ETS and p53/p63, to be consistently enriched and highly correlated with the expression of specific genes that define a given subtype. To dissect the functional role of enhancers and their regulators in directing expression, we have defined global cistromes of two key HNSCC-enriched TFs, ETS1 and dNp63, by ChIP-seq and RNA-seq experiments in representative cell lines. These studies, boosted by integrated meta-analysis of HNSCC patient datasets, reveal that the master TF-dependent core gene signatures are associated with key cellular processes that are specifically enriched in HNSCC subtypes. This includes EMT and invasion for the mesenchymal, inflammation for the basal, and drug metabolism processes in the HPV+ve atypical subtype. Finally, we have leveraged network analysis and drug discovery algorithms to identify novel subtype-specific small molecules that can potentially disrupt the CRMs in targeted fashion. Our systematic approach to epigenomically define and characterize the hardwired underpinnings of tumor heterogeneity has unveiled TF-dependent pathways and downstream effectors that are primed for future drug discovery and clinical trials. Citation Format: Christian Gluck, Akinsola Oyelakin, Alexandra Glathar, Michael Buck, Rose-Anne Romano, Satrajit Sinha. Genomic and epigenomic analysis reveal a distinct and targetable transcriptional signature of HNSCC subtypes [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr A26.