O’cathail, SM;
Wu, CH;
Thomas, R;
Hawkins, MA;
Maughan, TS;
Lewis, A;
(2021)
NRF2 Mediates Therapeutic Resistance to Chemoradiation in Colorectal Cancer through a Metabolic Switch.
Antioxidants
, 10
(9)
, Article 1380. 10.3390/antiox10091380.
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Abstract
Radiation resistance is a significant clinical problem in rectal cancer treatment, the mechanisms of which are poorly understood. NRF2 signalling is known to contribute to chemo/radioresistance in some cancers, but its role in therapeutic resistance in colorectal cancer (CRC) is unexplored. Using siRNA and CRiSPR/Cas9 isogenic CRC cell lines, we investigated the effect of the knockdown and upregulation of the NRF2 pathway on chemo-radiosensitivity. Poly (A) enriched RNA sequencing and geneset enrichment analysis (GSEA) were carried out on both sensitive and resistant cell models for mechanistic insights. Finally, a cohort of rectal patient samples was profiled to understand the clinical relevance of NRF2 signalling. Radioresistant cell lines were significantly radiosensitised by siRNA knockdown (SW1463, SER10 1.22, ANOVA p < 0.0001; HT55, SER10 1.17, ANOVA p < 0.01), but not the (already) radiosensitive HCT116. The constitutive activation of NRF2 via a CRISPR Cas9 NFE2L2 mutation, E79K, induced radioresistance in HCT116 (SER10 0.71, ANOVA, p < 0.0001). GSEA demonstrated significant opposing metabolic dependencies in NRF2 signalling, specifically, the downregulation of amino acid and protein synthesis with low levels of NRF2 and upregulation with over expression. In a clinical cohort of 127 rectal patients, using a validated mRNA signature, higher baseline NRF2 signalling was associated with incomplete responses to radiation higher final neoadjuvant rectal (NAR) score (OR 1.34, 95% C.I. 1.01–1.80, LRT p-value = 0.023), where high NAR indicates poor radiation response and poor long-term prognosis. This is the first demonstration of NRF2-mediated radiation resistance in colorectal cancer. NRF2 appears to regulate crucial metabolic pathways, which could be exploited for therapeutic interventions.
| Type: | Article |
|---|---|
| Title: | NRF2 Mediates Therapeutic Resistance to Chemoradiation in Colorectal Cancer through a Metabolic Switch |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.3390/antiox10091380 |
| Publisher version: | https://doi.org/10.3390/antiox10091380 |
| Language: | English |
| Additional information: | © 2021 MDPI. This is an open access article distributed under the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). |
| Keywords: | NRF2; radiation; metabolism; therapeutic resistance |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > UCL BEAMS UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Med Phys and Biomedical Eng |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10134409 |
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