Abstract A042: Targeting vulnerabilities arising from global DNA hypomethylation in cancer

Abstract

Abstract Background: DNA methylation alterations are a universal feature of cancer. In addition to site specific gain of DNA methylation (hypermethylation), a global loss of methylation (hypomethylation) was noted in most cancer genomes. Whereas numerous studies have focused on the role of hypermethylation in disease progression, less is known about the biology of hypomethylation in cancer. Recently, we have identified tumors across all major cancer types that are characterized by severe loss of DNA methylation. Our preliminary data suggest that these DNA hypomethylated cancers (hereafter DHMCs) show distinct alterations influencing gene expression and tumor microenvironment composition. Objective: We hypothesize that since DNA methylation is critical for genome organization and gene expression. Severe global hypomethylation is likely to result in distinct epigenomic and genomic alterations. We therefore investigate common molecular changes associated with DNA hypomethylation to develop novel therapeutic approaches targeting unique vulnerabilities arising in DHMCs. Study design: To delineate the biology of DHMCs, we determined methylation changes with validated orthogonal methods in large representative cohorts of patient samples (The Cancer Genome Atlas (TCGA), University of Washington rapid autopsy cohorts), patient derived xenografts and cancer cell lines. We assessed the patterns of common molecular alterations by performing genome wide epigenome mapping experiments and by defining common driver gene events in DHMCs. We further determined tumor cell intrinsic therapeutic vulnerabilities in broad pharmacologic and CRISPR-Cas9 genomic screens. Results: We observed that DNA hypomethylation is a relatively common feature of solid tumors affecting overall 15-20% of all cancers, with highest rates observed in urothelial, melanoma, hepatocellular and lung and head and neck squamous cell carcinoma. In in vivo tumor models of DHMCs, we observe distinct shifts in epigenetic states upon DNA hypomethylation. Most notably, we found that DHMCs are characterized by unique intrinsic drug sensitivities to drug classes affecting core histone levels. Impact: This is the first study to show druggable vulnerabilities arising from DNA hypomethylation. Collectively, these studies define a novel epigenetic subtype of cancer, determine its clinical and molecular features, and pave the way for new targeted therapies. Citation Format: Pallabi Mustafi, Brian Hanratty, Ilsa Coleman, Radhika Patel, Adil Mohamed, Jay Sarthy, Gavin Ha, Michael Haffner. Targeting vulnerabilities arising from global DNA hypomethylation in cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A042.