Dysregulation and Epigenetic Reprogramming of NRF2 Signaling Axis Promote Acquisition of Cisplatin Resistance and Metastasis in Head and Neck Squamous Cell Carcinoma

Abstract

Purpose: CDDP based chemotherapy is a first-line treatment for patients with advanced head and neck squamous cell carcinomas (HNSCCs), despite a high rate of treatment failures, acquired resistance and subsequent aggressive behavior. The purpose of this study was to delineate the mechanism of CDDP resistance and metastasis in HNSCC. We investigated the role of NRF2 pathway activation as a driven event for tumor progression and metastasis of HNSCC. Experimental Design: Human HNSCC cell lines that are highly resistant to CDDP were generated. Clonogenic survival assays and a mouse model of oral cancer were used to examine the impact of NRF-2 activation in vitro and in vivo on CDDP sensitivity and development of metastasis. Western blotting, immunostaining, whole exome sequencing, single cell transcriptomic and epigenomic profiling platforms were performed to dissect clonal evolution and molecular mechanisms Results: Implantation of CDDP resistant HNSCC cells into the tongues of nude mice resulted in a very high rate of distant metastases. The CDDP resistant cells had significantly higher expression of NRF2 pathway genes in the presence of newly acquired KEAP1 mutations, or via epigenomic activation of target genes. Knockdown of NRF2 or restoration of the wtKEAP1 genes re-sensitized resistant cells to CDDP and decreased distant metastasis. Finally, treatment with inhibitor of GLS1, a NRF2 target gene, alleviated CDDP resistance. Conclusions: CDDP resistance and development of distant metastasis are associated with dysregulated and epigenetically reprogrammed KEAP1-NRF2 signaling pathway. A strategy targeting KEAP1/NRF2 pathway or glutamine metabolism deserves further clinical investigation in patients with CDDP resistant head and neck tumors.

New perspectives on biology, disease progression, and therapy response of head and neck cancer gained from single cell RNA sequencing and spatial transcriptomics

“…Thus, a comprehensive understanding of the underlying mechanisms is crucial for improving treatment strategies and prolonging survival of cancer patients. In this context, single-cell analyses were performed to elucidate how cells react to chemotherapy, radiotherapy, targeted therapy, and ICI therapy in HNSCC [94,[112][113][114][115][116][117][118][119][120].…”

“…Osman et al investigated cisplatin resistance in a human HNSCC cell line by scRNAseq and found p53 signaling, cell cycle, senescence, platinum resistance, and FoxO signaling to be activated in cisplatin resistant cells [112]. Further, an epigenetically primed subpopulation, driven by NRF2, a protein involved in regulation of anti-oxidative stress response and epigenomic changes, was identified, potentially linking cellular oxidative stress response and cisplatin resistance [112].…”

“…Osman et al investigated cisplatin resistance in a human HNSCC cell line by scRNAseq and found p53 signaling, cell cycle, senescence, platinum resistance, and FoxO signaling to be activated in cisplatin resistant cells [112]. Further, an epigenetically primed subpopulation, driven by NRF2, a protein involved in regulation of anti-oxidative stress response and epigenomic changes, was identified, potentially linking cellular oxidative stress response and cisplatin resistance [112]. Among eight patients with HPSCC, responsiveness to a therapy comprising taxol, cisplatin, 5-fluorouracil, and cetuximab was associated with a higher number of infiltrating immune cells both before and after therapy as determined by scRNAseq and multiplex immunohistochemistry [118].…”

ANKRD2 expression combined with TNFRSF19 expression for evaluating the prognosis of oral squamous cell carcinoma patients

“…Xu et al found that the cisplatin resistance-regulating roles of the TNFAIP2/KEAP1/NRF2/JNK axis in HNSCC, suggesting that TNFAIP2 might be a potential target of HNSCC cisplatin resistance [ 10 ]. Osman et al demonstrated that cisplatin resistance and development of distant metastasis are associated with dysregulated and epigenetically reprogrammed KEAP1-NRF2 signaling pathway [ 11 ]. Although many discoveries have emerged concerning the reason for cisplatin resistance in oral cancer patients [ 12 ], the mechanism is still not clearly understood.…”

Construction of a nomogram for predicting HNSCC distant metastasis and identification of EIF5A as a hub gene

“…Multiple genes are involved in HNSCC distant metastasis. For instance, Osman et al reported that the KEAP1/NRF2 pathway is related to HNSCC metastasis and drug resistance, while Ming Zhang et al reported that FOSL1 promotes the distant metastasis of HNSCC by promoting its transcription 12 , 13 .…”