NRF2 signaling drives chemoresistance in NSCLC and glioblastoma.

Although great advances have been made in cancer treatment, lung cancer and glioblastoma patients continue to present a dismal prognosis, mainly due to drug resistance. Evidence suggests that NRF2 and glutathione (GSH) play a fundamental role in chemotherapy resistance. Notably, GSH depletion by buthionine sulfoximine (BSO) has been demonstrated to sensitize human tumor cells to a wide variety of chemotherapeutic agents. However, the incorporation of BSO into standard chemotherapy regimens lacks a robust clinical rationale. In this study, we aimed to investigate the mechanisms governing differential sensitivity to chemotherapy in lung cancer and glioblastoma cells to identify novel strategies to enhance outcomes in these malignancies. For this purpose, we analyzed several cellular responses in cell lines exhibiting distinct sensitivities to temozolomide (TMZ) and cisplatin. Our findings indicate that the NRF2/GSH pathway plays a crucial role in TMZ and cisplatin resistance and that pharmacological GSH depletion enhances the sensitivity of NRF2-high, chemotherapy-resistant cells to these agents. Furthermore, BSO in combination with TMZ or cisplatin enhanced chemotherapy-induced cytotoxicity and engaged both apoptotic and ferroptosis-related responses in NSCLC cells. These findings provide preclinical evidence supporting further investigation of NRF2/GSH targeting as a strategy to overcome chemotherapy resistance.