Abstract C045: Exploring EGLN1/PHD2 role in KRAS mutated lung cancer: insights into mitochondrial modulation and therapeutic opportunities

Abstract Lung cancer is the first cause of cancer-related death. In lung adenocarcinoma (LUAD), different genetic alterations can be targeted with small-molecule compounds, including the KRAS inhibitors. However, the development of resistance mechanisms indicates that exploring new target genes is still an urgent medical need. Through an integrative approach, combining functional genomics and bioinformatics, we identified EGLN1 as a novel druggable dependency gene in KRAS-mutated LUAD. The EGLN1 gene encodes the PHD2 enzyme, the oxygen sensor regulating HIF transcription factor activity. EGLN1 is overexpressed in tumor tissue and associated with worse prognosis in patients. In LUAD cell lines, EGLN1 supports proliferation, migration, colony formation and 3D growth. EGLN1 knockout leads to tumor growth impairment in xenograft models. We showed that EGLN1 acts at least through two different molecular mechanisms, one HIF1a dependent and one HIF1a independent. Through integrative analysis of transcriptomic and proteomic profiles, we identified a panel of mitochondrial genes deregulated independently of HIF1a. Strikingly, EGLN1 KO leads to aberrant mitochondria morphology and profound impairment of mitochondrial respiration. These results are particularly intriguing, since EGLN1 inhibitors are currently in use for anemia and could be easily repurposed to the cancer setting. To assess this possibility, we proceeded to a pre-clinical validation of these compounds both in LUAD cell lines and in primary samples. To this end, we setup a platform to isolate and expand patients-derived organoid cultures (PDO) from LUAD patients. We confirmed that EGLN1 inhibitors restrain cancer cells growth both in cell lines and in PDO cultures, having a prominent effect in the KRAS-mutated background. Overall, we employed a functional genomics approach to identify and validate EGLN1 as a novel therapeutic target in KRAS-mutated lung cancer. Our results uncover a pro-oncogenic role of EGLN1 in lung cancer, partially relying on a HIF-independent mechanism. Moreover, our work suggests that EGLN1 inhibitors, already in clinical trials for anemia, could be effective in KRAS-driven lung cancer treatment. Overall, our emerging data lay the basis for the development of new therapeutic strategies in KRAS-mutated adenocarcinoma patients. Citation Format: Alessandra Grieco, Giulio Verna, Silvia Strocchi, Valentina Fantini, Emanuele Vitale, Veronica Manicardi, Federica Torricelli, Giacomo Santandrea, Eleonora Zanetti, Davide Nicoli, Alessandro Corbelli, Fabio Fiordaliso, Giovanna Damia, Francesca Ricci, Konstantinos Lefkimmiatis, Massimiliano Paci, Alessia Ciarrocchi, Valentina Sancisi. Exploring EGLN1/PHD2 role in KRAS mutated lung cancer: insights into mitochondrial modulation and therapeutic opportunities [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C045.