Abstract 1259: Studying the role of chromatin accessibility in lineage plasticity of Rb1-deficient EGFR-mutant lung adenocarcinoma

Abstract Lung cancer is the leading cause of cancer mortality worldwide. Mutations in the epidermal growth factor receptor (EGFR) account for approximately 27% of all lung adenocarcinoma (LUAD) cases. Osimertinib is a third generation EGFR tyrosine kinase inhibitor (TKI) that is, initially, remarkably effective at treating patients with EGFR mutant LUAD. Acquired resistance to Osimertinib develops in most patients leaving few therapeutic options. This highlights an unmet clinical need to prevent/combat Osimertinib resistance. Lineage plasticity, an epigenetic process characterized by transcriptional heterogeneity and molecular adaptation, has been identified as a mechanism of Osimertinib resistance in the clinic. As more potent targeted therapeutics are deployed for treating cancer patients, plasticity-based resistance will likely increase. The molecular basis of lineage plasticity is not well understood, and greater characterization of lineage plasticity is imperative for developing new therapies aimed at preventing/reversing plasticity-associated resistance. Loss of the major tumor suppressor gene Rb1 has previously been implicated in lineage plasticity of several different cancers including LUAD. How loss of Rb1 contributes towards lineage plasticity remains poorly understood. Rb1 is a known regulator of chromatin accessibility, playing a key role in recruiting epigenetic writers to silence gene expression through repressive methylation of histones and DNA. Whether altered chromatin regulation in the absence of Rb1 contributes to LUAD lineage plasticity has not been examined. To begin examining the chromatin accessibility/plasticity axis in vitro, we are developing a PROTAC-based, rapidly inducible Rb1 protein degradation system utilizing the dTAG degron system to characterize the dynamics of molecular changes subsequent to Rb1 loss of function. Changes in chromatin accessibility will be assessed by micrococcal nuclease digestion and a novel nuclear propidium iodide staining technique. Plasticity will be assessed indirectly by in vitro colony formation and time to resistance assays. The timing of changes in transcriptional plasticity and chromatin accessibility will be compared. The goal of this project is to gain a greater understanding of how Rb1 loss impacts chromatin structure and subsequently, whether increased chromatin accessibility promotes plasticity-associated Osimertinib resistance. Citation Format: Bradley Balk, David W. Goodrich. Studying the role of chromatin accessibility in lineage plasticity of Rb1-deficient EGFR-mutant lung adenocarcinoma [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 1259.