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

Authors

Abdullah A Osman
Emre Arslan
Mason Bartels
Chieko Michikawa
Antje Lindemann
Katarzyna Tomczak
Wangjie Yu
Vlad Sandulache
Wencai Ma
Li Shen
Jing Wang
Anand K Singh
Mitchell J Frederick
Nakia D Spencer
Jeffery Kovacs
Timothy Heffernan
William F Symmans
Kunal Rai
Jeffrey N Myers

Publication Date

4-3-2023

Journal

Clinical Cancer Research

Abstract

PURPOSE: Cisplatin (CDDP)-based chemotherapy is a first-line treatment for patients with advanced head and neck squamous cell carcinomas (HNSCC), despite a high rate of treatment failures, acquired resistance, and subsequent aggressive behavior. The purpose of this study was to study 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 NRF2 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 wild-type KEAP1 genes resensitized resistant cells to CDDP and decreased distant metastasis (DM). Finally, treatment with inhibitor of glutaminase-1, a NRF2 target gene, alleviated CDDP resistance.

CONCLUSIONS: CDDP resistance and development of DM 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.

Keywords

Animals, Humans, Mice, Antineoplastic Agents, Cell Line, Tumor, Cisplatin, Drug Resistance, Neoplasm, Epigenesis, Genetic, Epigenomics, Head and Neck Neoplasms, Kelch-Like ECH-Associated Protein 1, Mice, Nude, NF-E2-Related Factor 2, Signal Transduction, Squamous Cell Carcinoma of Head and Neck

Comments

Supplementary Materials

Data Availability Statement

PMID: 36689560