Targeting ferroptosis pathway to overcome erlotinib resistance

Thesis

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. For advanced NSCLC, targeted therapies are often recommended to improve prognosis by acting on specific genetic mutations. Epidermal growth factor receptor (EGFR) is frequently hyperactivated in NSCLC, and EGFR tyrosine kinase inhibitors have been used clinically for decades to treat patients harbouring EGFR mutations. However, acquired resistance commonly develops, reducing therapeutic effectiveness. To address this challenge, we investigated whether erlotinib-resistant NSCLC could be targeted through ferroptosis, an iron-dependent cell death that can be promoted by radiation. Our RNA sequencing data revealed that genes involved in lipid metabolism and iron transport, key components of the ferroptosis pathway, were significantly dysregulated in erlotinib-resistant cells, along with those associated with tumour cell invasion. Western blot analysis further demonstrated that these cells have a compromised capacity to manage lipid peroxidation, likely due to lower xCT/SLC7A11 expression, a key regulator of ferroptosis resistance. Our data showed that erlotinib-resistant cells were more sensitive to erastin- and radiation-induced ferroptosis. We also found that erlotinib-resistant cells exhibited significantly higher lipid peroxidation and lipid droplet accumulation, which were further enhanced following ferroptosis induction. To validate our data in a physiologically relevant setting, we performed in vivo studies using mouse subcutaneous xenograft models. Consistent with in vitro data, erlotinib-resistant tumours were more sensitive to ferroptosis induced by the combination of radiation with the ferroptosis inducer IKE. Our research demonstrated increased ferroptotic susceptibility in erlotinib-resistant NSCLC, suggesting a novel therapeutic vulnerability. It provides a potential strategy for overcoming erlotinib resistance in NSCLC and highlights the role of ferroptosis in the treatment of erlotinib-resistant cancer.

Authors: Hou, T

• DOI: 10.5287/ora-kzzdpddpr
• Type of award: MSc by Research
• Level of award: Masters
• Awarding institution: University of Oxford
• Language: English
• Keywords: lung cancer; targeted therapy; ferroptosis; radiotherapy; drug resistance
• Subjects: Radiotherapy; Cancer; ferroptosis