Abstract 7303: Activation of HIF1ɑ drives oxidative stress and promotes deep senescence in <i>EGFR</i> -mutant NSCLC drug tolerant persister cells

Abstract Non-small cell lung cancers with oncogenic mutations in EGFR (exon 19 deletions or L858R substitutions) are sensitive to EGFR tyrosine kinase inhibitors (TKIs), which induce deep and durable responses in the majority of patients. However, despite these responses, the development of acquired resistance to EGFR TKIs is inevitable. Preclinical studies have implicated a role for drug-tolerant persister (DTP) cells in the development of acquired drug resistance. DTPs are a subpopulation of cancer cells that survive initial TKI therapy by entering a reversible, slow-cycling or quiescent state. Mechanistically, DTPs leverage reversible, non-genomic mechanisms, including epigenetic plasticity, activation of survival signaling pathways, and lineage switching, to maintain a drug-tolerant state. Importantly, DTP cells can undergo further evolution and acquire mechanisms of drug resistance that drive disease relapse. To identify vulnerabilities of DTP cells, we characterized DTP cells in patient-derived xenograft models of EGFR-mutant NSCLC and malignant pleural effusions from patients treated with EGFR TKIs. We observed that HIF1-ɑ (hypoxia-inducible factor 1 alpha) signaling was consistently downregulated in DTP cells across models and patients. Unexpectedly, stabilization and reactivation of HIF-1α with the prolyl hydroxylase inhibitor, resensitized DTP cells to EGFR TKIs and suppressed the emergence of drug-resistant clones. Mechanistically, HIF-1 ɑreactivation increases oxidative stress in DTPs and promotes entry to an irreversible deep senescence state. These results add to a growing body of evidence that mitigation of oxidative stress is critical for DTP survival and suggest that reactivation of HIF-1α signaling may provide a therapeutic strategy to prevent emergence of resistance in EGFR-mutant NSCLC. Citation Format: Radhika Koranne, Avishai Wizel, Aimee J. Gleason, Justine Bellier, Heidie Cabanos, Sarah Reeves, Luke Boland, Yotam Drier, Aaron N. Hata. Activation of HIF1ɑ drives oxidative stress and promotes deep senescence in EGFR-mutant NSCLC drug tolerant persister cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7303.