Abstract Rare tumor cell populations can evade cancer therapies, ultimately driving drug resistance and relapse. These resilient populations, termed “persisters, ” display distinct molecular states compared to the bulk tumor. While some persisters acquire genetic mutations that confer growth advantage, others undergo non-genetic remodeling that enhances cellular plasticity and fitness. Previous studies suggest that stochastic gene activation promotes persister survival (Shaffer et al. , Nature 2017; Goyal et al. , Nature 2023), yet the master regulators of this plasticity remain undefined. Using DNA barcoding, we demonstrate that pre-determined, non-stochastic persisters exist in KRAS-mutant non-small cell lung cancer (NSCLC) treated with the KRAS G12C inhibitor sotorasib. These clones repopulate the tumor without harboring recurrent genetic alterations. By isolating single clones destined to persist or go extinct, and profiling their transcriptomes and chromatin accessibility, we found that persister clones activate an interferon-γ (IFNγ) transcriptional signature accompanied by increased chromatin accessibility at sites enriched for the transcription factors IRF1 and ZNF384. Functionally, ectopic ZNF384 expression converted the entire cell population into a resistant state, while IRF1 knockout prevented persister formation. Cleavage Under Targets 2025 Dec 4-6; Albuquerque, NM. Philadelphia (PA): AACR; Cancer Res 2025;85 (23Suppl): Abstract nr B014.
Nimbalkar et al. (2025) studied this question.