KEAP1/NRF2 Mutations in Stem Cells Define an Aggressive Subset of Head and Neck Cancer Patients Who Have a Poor Prognosis, Lung Metastasis, and Therapeutic Failure

Sep 24, 2026

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Mutations in Keap1/Nrf2 drive abnormal cell growth in head and neck cancer, but their clinical significance in head and neck cancer stem cells (HN-CSCs) remains unclear. Freshly resected tumors from patients (n=50) provided cancerous HN-CSCs and benign stem cells, purified by flow cytometry sorting and analyzed for Keap1/Nrf2 alterations. Thirteen tumors contained Keap1/Nrf2 mutations in HN-CSCs, which correlated with rapid lung metastasis, worse treatment outcomes, and shorter progression-free survival and overall survival. Associations were linked to mutation-enriched HN-CSCs among fast progressors and suggested value for molecular genotyping to guide personalized therapy.

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CategoryHealthcare

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cancers Article KEAP1/NRF2 Mutations in Stem Cells Deﬁne an Aggressive Subset of Head and Neck Cancer Patients Who Have a Poor Prognosis, Lung Metastasis, and Therapeutic Failure Syed S. Islam 1,2, *, Bedri Karakas 3, Abdelilah Aboussekhra 1 and Abu Shadat M. Noman 4 Citation: Islam, S.S.; Karakas, B.; Aboussekhra, A.; Noman, A.S.M. KEAP1/NRF2 Mutations in Stem Cells Deﬁne an Aggressive Subset of Head and Neck Cancer Patients Who Have a Poor Prognosis, Lung Metastasis, and Therapeutic Failure. Cancers 2023, 15, 5006. [https://doi.org/](https://doi.org/)[ ](https://doi.org/)[10.3390/cancers15205006](10.3390/cancers15205006) Academic Editor: Claudia Maletzki Received: 23 August 2023 Revised: 5 October 2023 Accepted: 9 October 2023 Published: 16 October 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . 1 Department Molecular Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia 2 Faculty of Medicine, Al-Faisal University, Riyadh 11533, Saudi Arabia 3 3 B & B Bio, 4 Professional Drive, Gaithersburg, MD 20879, USA 4 Department Biochemistry and Molecular Biology, The University of Chittagong, Chittagong 4331, Bangladesh * Correspondence: [sislam83@kfshrc.edu.sa](sislam83@kfshrc.edu.sa); Tel.: +966-50-012-9242 Simple Summary: Mutations in head and neck cancer result in abnormal tumor cell growth, increase the risk of distant metastasis, and lead to therapeutic failure. Progenitor cells, head and neck cancer stem cells, and bulk tumor cells may all harbor these mutations, and identifying the mutations in stem cells may facilitate stratifying patients who are likely to beneﬁt from treatment. Patients with head and neck cancer whose tumor exhibits Keap1/Nrf2 mutations in their stem cells are signiﬁcantly more likely to develop rapid lung metastasis and fail treatment. Our ﬁndings suggest a molecular genotyping of head and neck cancer stem cells, which may facilitate personalized treatment strategies and assist in identifying patients who would beneﬁt from chemotherapy, radiotherapy, and targeted therapies. Abstract: Mutations in Keap1/Nrf2 in head and neck cancer result in abnormal cell growth. Progenitor cells, bulk tumor cells, and head and neck cancer stem cells (HN-CSCs) may all harbor these mutations. Nevertheless, whether Keap1/Nrf2 mutations in HN-CSCs have an impact on clinical outcomes is unknown. Cancerous HN-CSCs and benign stem cells were obtained from freshly resected head and neck cancer patients (n = 50) via ﬂow cytometry cell sorting and tested for Keap1/Nrf2 mutations. The existence of Keap1/Nrf2 mutations in HN-CSCs, as well as their correlations with tumor mutations, pathologic tumor stage, tumor histologic grades, lung metastasis, treatment outcomes, and the patient's age and conditions, are assessed at the last follow-up visit. Thirteen tumors were found to have Keap1/Nrf2 mutations in their HN-CSCs. More than half of the lung metastases and disease progression occurred in HN-CSCs with mutations. Patients whose tumors carried Keap1/Nrf2 mutations in their HN-CSCs had signiﬁcantly shorter progression-free survival, overall survival, and time of treatment failure than their non-HN-CSC counterparts. These associations were partly driven by HN-CSCs, in which Keap1/Nrf2 mutations were overrepresented in fast progressors and associated with an increased risk of disease progression. Our ﬁndings suggest that molecular genotyping of HN-CSCs may facilitate personalized treatment strategies and assist in identifying patients who are likely to beneﬁt from chemotherapy. Keywords: Keap1; Nrf2; fast progressors; head and neck cancer; HN-CSCs 1. Intro

FAQs

What is the main question the study addresses about Keap1/Nrf2 mutations in HN-CSCs?

Whether Keap1/Nrf2 mutations specifically in head and neck cancer stem cells affect clinical outcomes in head and neck cancer patients.

How were HN-CSCs and stem cells obtained and analyzed in this study?

Cancerous HN-CSCs and benign stem cells were obtained from freshly resected head and neck cancer patients (n=50) using flow cytometry cell sorting, then tested for Keap1/Nrf2 mutations.

What clinical outcomes were worse in patients whose tumors had Keap1/Nrf2 mutations in HN-CSCs?

They had significantly shorter progression-free survival, overall survival, and time to treatment failure, along with a higher likelihood of rapid lung metastasis and disease progression.

Sep 24, 2026

Uploaded by Aran