Cisplatin-induced genetic alterations in KEAP1 promote therapeutic resistance in head and neck squamous cell carcinoma

Cisplatin (CDDP) resistance remains a major challenge in the treatment of recurrent head and neck squamous cell carcinoma (HNSCC). The KEAP1-NRF2 system, a central regulator of cellular redox homeostasis, is frequently altered in cancer, but its contribution to acquired CDDP resistance in HNSCC remains to be clarified. To address this, we investigated NRF2 activation in CDDP resistance using seven parental (P) HNSCC cell lines and their CDDP-resistant (CR) derivatives. Among these P-CR pairs, three CR lines exhibited elevated NRF2 expression; two harbored KEAP1 mutations, and one had an NFE2L2 mutation that were present in both P and CR lines. These NRF2-high CR lines showed upregulation of NRF2 target genes and enrichment of xenobiotic metabolism and reactive oxygen species pathways. Mitomycin C (MMC), a cytotoxic agent for its synthetic lethality in NRF2-activated cancer cells, demonstrated strong cytotoxicity specifically in these NRF2-high CR lines. Immunohistochemical analysis on clinical samples found that high NRF2 expression was significantly associated with poor prognosis and was frequently observed in recurrent tumors following chemoradiotherapy with CDDP. These results suggest that CDDP therapy, while initially effective, may paradoxically promote tumor progression and therapeutic resistance by aberrantly activating the KEAP1-NRF2 axis. This redox-driven adaptation highlights a critical characteristic in NRF2-hyperactivated HNSCC that is exploitable by MMC treatment.