Abstract 2725: Noncanonical regulation of genes by KMT5C-H4K20me3 in EGFR inhibitor resistant non-small cell lung cancer

Abstract Lung cancer is the leading cause of all cancer-related deaths, with non-small cell lung cancer (NSCLC) making up ∼85% of lung cancer cases. Activating mutations in the epidermal growth factor receptors (EGFR) are associated with NSCLC development, comprising ∼32% of patients. Standard treatment for NSCLC patients involves targeting EGFR mutations with EGFR inhibitors (EGFRi), yet most patients develop resistance to EGFRi over time. Approximately 55% of the mechanisms involved in EGFRi resistance involve EGFR T790M secondary mutations; however, nearly 15% of these mechanisms are unknown. We have previously shown that the loss of KMT5C drives resistance to EGFRi in EGFR-mutant NSCLC cells. Patient data further supports that the KMT5C transcript level is downregulated following resistance. KMT5C is a histone methyltransferase that catalyzes the trimethylation of H4K20 (H4K20me3), a repressive modification historically known for the involvement of heterochromatin formation and maintenance. KMT5C recruitment through H4K20me3 to heterochromatic regions is a well-known mechanism occurring in H3K9me3-dependent manner. Our preliminary data also suggests KMT5C-H4K20me3 is associated with the regulation of gene-rich euchromatin regions; yet the mechanism of recruitment remains unknown. We hypothesize that recruitment of KMT5C to euchromatin is distinct from the mechanism involved in KMT5C recruitment to heterochromatin. Here, we study the interactome of KMT5C using an unbiased proximity labeling technique, BioID, and aim to identify factors that form a novel complex with KMT5C to enable the recruitment of KMT5C to its target genes in euchromatic regions that drive resistance to EGFRi. Citation Format: Alexandra Glaws, Jihye Son, Andrea Kasinski. Noncanonical regulation of genes by KMT5C-H4K20me3 in EGFR inhibitor resistant 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 2725.