Abstract 2719: Decoding role of KMT5C-H4K20me3 in EGFRi resistance in non-small cell lung cancer

Abstract Epigenetic dysregulation has recently been recognized as a new hallmark of cancer, with dysregulation of chromatin remodelers estimated to affect 10-20% of cancer. Thus, understanding how epigenetic-based mechanisms contribute to cancer initiation and progression is critical. KMT5C is a histone methyltransferase that catalyzes histone H4 lysine 20 trimethylation (H4K20me3), which has historically been associated with formation and maintenance of constitutive heterochromatin regions. Perturbations in KMT5C-H4K20me3 in cancer has been extensively characterized, including our own work in which we discovered that loss of KMT5C promotes development of resistance to EGFR inhibitor (EGFRi) in EGFR-mutant non-small cell lung cancer (NSCLC) cells. Patient data further supports that the KMT5C transcript level is downregulated following resistance to osimertinib, a third-generation EGFRi. Here, we present data to support a non-canonical role for H4K20me3 where it regulates genes outside of heterochromatin. Notably, deposition of H4K20me3 in these regions occurs without the need for H3K9me3, which was thought to be a prerequisite for H4K20me3 deposition. This uniquely deposited H4K20me3 is associated with pathways such as DNA replication and cell cycle transition. H4K20me3 also co-localizes with activating histone modifications including H3K4me3, requiring additional studies to evaluate how dysregulation of H4K20me3 is involved in transcriptional programming in NSCLC to promote EGFRi resistance. Finally, we identifed the KMT5C interactome, which reveals novel interacting partners of KMT5C, potentially uncovering mediators of KMT5C dysregulation. Taken together, our findings unveil novel roles of KMT5C-H4K20me3 in regulating chromatin architecture and suggest etiological mechanism of KMT5C-driven EGFRi resistance in NSCLC. Citation Format: Jihye Son, Alexandra Glaws, Christina Davidson, Ching-Hua Shih, Paula Vertino, Andrea Kasinski. Decoding role of KMT5C-H4K20me3 in EGFRi resistance in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2719.