Abstract 6804: Sanguinarine overcomes osimertinib resistance by inducing HMOX1-related ferroptosis in osimertinib resistant cells lines and tumors

Abstract Epidermal Growth Factor Receptor (EGFR) gene, as a crucial oncogenic driver, plays a significant role in the occurrence and progression of non-small cell lung cancer (NSCLC). Osimertinib, as the latest generation of EGFR tyrosine kinase inhibitors (TKIs), has shown remarkable efficacy not only in patients with EGFR-sensitive mutations but also in those with rare EGFR mutations. However, similar to patients treated with first- or second-generation EGFR-TKIs, those treated with osimertinib eventually develop resistance Therefore, it is crucial to investigate the mechanisms of resistance and identify novel, rational strategies and drugs to overcome acquired resistance. Here we demonstrated that Sanguinarine, a natural benzophenanthridine alkaloid derived from rhizomes of the plant species Sanguinaria canadensis, which induces ferroptosis in osimertinib-resistance cells, leading to cell death. In this study, we found that sanguinarine induced more cell death in osimertinib-resistant cell lines, compared to osimertinib-sensitive EGFR-mutant cell lines. RNA-seq showed that sanguinarine increased higher expression level of HMOX1 in osimertinib-resistant cell lines than osimertinib-sensitive EGFR-mutant cell lines. Moreover, compared to osimertinib-sensitive cell lines, sanguinarine induces more ROS production, increases Fe2+ concentration, and promotes more ferroptosis in osimertinib-resistant cell lines. Interestingly, we found that HMOX1 levels are elevated in tissues from patients with EGFRm NSCLC who relapsed from EGFR-TKI treatment. Also, Osimertinib and other EGFR-TKIs up-regulate HMOX1 expression in EGFRm NSCLSC cells and tumors. Enforced expression of an ectopic HMOX1 gene in Osimertinib-sensitive EGFRm NSCLC cells increased the sensitivity of cells to sanguinarine by inducing more ferroptosis, whereas knockdown of HMOX1 in Osimertinib-resistant cell lines conferred resistance to sanguinarine. Importantly, sanguinarine inhibited more effective in osimertinib resistant EGFRm NSCLC xenograft in vivo than in osimertinib sensitive models. Together, compared to osimertinib-sensitive cell lines, sanguinarine induces more ROS production and increases Fe2+ concentration results in more ferroptosis in osimertinib-resistant cell lines. This difference may be due to the overexpression of HMOX1 in Osimertinib-resistant cells, making them more susceptible to the effects of sanguinarine. Citation Format: Rongzhong Xu, Liubing Lin. Sanguinarine overcomes osimertinib resistance by inducing HMOX1-related ferroptosis in osimertinib resistant cells lines and tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6804.