Abstract B018: ZNF384 Orchestrates Cell-State Reprogramming and Kinome Remodeling in KRAS G12C Inhibitor Resistance

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&RUN analysis revealed drug-induced ZNF384 occupancy at promoter and enhancer regions, including the promoter of RasGEF domain family member 1B (RasGEF1B), a potential contributor to ERK reactivation in persister cells. Together, these findings identify ZNF384 as a tumor-intrinsic master regulator linking IFNγ signaling, transcriptional plasticity, and ERK reactivation, offering mechanistic insight into the non-genetic evolution of drug tolerance and resistance in KRAS-mutant NSCLC. Citation Format: Chendi Li, Anahita Nimbalkar, Christopher J. Graser, Melissa Vieira, Mohammed U. Syed, Qian Qin, Barbara Karakyriakou, Chris Ott, Luca Pinello, Franziska Michor, Aaron Hata. ZNF384 Orchestrates Cell-State Reprogramming and Kinome Remodeling in KRAS G12C Inhibitor Resistance [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_1):Abstract nr B018.