Abstract Resistance to KRAS inhibitors in KRAS-mutant non-small cell lung cancer (NSCLC) has been attributed to both genetic alterations (Tanaka et al. , 2021; Awad et al. , 2021) and non-genetic mechanisms, including reactivation of AKT (Misale et al. , 2019), wild-type RAS (Ryan et al. , 2022), MAPK signaling, or YAP signaling (Hagenbeek et al. , 2023). However, a unifying master regulator of therapy-induced kinome reprogramming has not been identified. Because kinome rewiring often emerges from therapy-induced cell-state transitions, we hypothesized that specific tumor subclones can adopt alternative cell states that enable MAPK reactivation and ultimately drive relapse. Using DNA barcoding, we show that KRAS-mutant NSCLC treated with the KRAS G12C inhibitor sotorasib contains pre-existing, non-stochastic drug-tolerant persister clones that later repopulate the tumor without acquiring recurrent genetic alterations. By isolating hundreds of single-cell-derived clones fated to persist or go extinct and performing transcriptomic and chromatin accessibility profiling, we found that persister clones upregulate an interferon-γ (IFNγ) transcriptional program alongside increased chromatin accessibility at sites enriched for the transcription factor ZNF384. Functionally, ectopic ZNF384 expression converted the entire population into a drug-resistant state, whereas ZNF384 knockout reduced cellular plasticity, sensitized persister-fated clones to sotorasib, and decreased RSK phosphorylation, an effector downstream of ERK. CUT 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (5Suppl₁): Abstract nr B018.
Li et al. (2026) studied this question.