Abstract B016: A novel epigenetic factor is required for the acquisition of TKI resistance in lung adenocarcinoma via the regulation of oncogene amplicons

Abstract

Lung cancer is the leading cause of cancer-related death worldwide and affects over 2 million people each year. In lung adenocarcinoma (LUAD), somatic activating mutations of epidermal growth factor receptor (EGFR) occur in approximately 15% of patients. The first-line therapy for patients with EGFR-mutant LUAD is administration of osimertinib, an EGFR tyrosine kinase inhibitor (TKI). While many patients’ tumors initially respond to osimertinib treatment, resistance inevitably develops in most cases, which is a major challenge that hinders treatment efficacy. One common mechanism of resistance to osimertinib is the amplification of oncogenes, such as MET, HER2, and RET. Despite the high prevalence of oncogene amplifications in resistant tumors, the mechanisms that control oncogene amplification and transcription are poorly understood. Recent work has shown that oncogenes are frequently amplified on extrachromosomal DNA (ecDNA), which are circularized and highly amplified DNA sequences that are present in at least 14% of human cancers. Additional studies have implicated ecDNA amplification in the acquisition of resistance to TKIs, yet the mechanisms through which ecDNA is regulated are largely unknown. In the present study, we have identified a novel epigenetic factor that promotes the acquisition of TKI resistance through the organization and transcription of oncogene amplicons, some of which occur on ecDNA. To determine whether this factor binds to DNA, we used and found that it is enriched at the promoters of amplified oncogenes. Further, we performed protein immunoprecipitation followed by mass spectrometry and identified multiple candidate interacting factors, such as histone readers and components of the cohesin machinery. Depletion of this epigenetic factor prevents the acquisition of TKI resistance and leads to reduced transcription of oncogene amplicons. Thus, we propose a novel mechanism that promotes the acquisition of TKI resistance via the spatial organization and transcription of oncogene amplicons. Citation Format: Rebecca M. Starble, Eric G. Sun, Tyler B. Jensen, Rana Gbyli, Ning Sun, Andrew Z. Xiao. A novel epigenetic factor is required for the acquisition of TKI resistance in lung adenocarcinoma via the regulation of oncogene amplicons. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B016.