NRF2 activation confers resistance to eIF4A inhibitors in cancer therapy Journal Article
| Authors: | Sanghvi, V. R.; Mohan, P.; Singh, K.; Cao, L.; Berishaj, M.; Wolfe, A. L.; Schatz, J. H.; Lailler, N.; de Stanchina, E.; Viale, A.; Wendel, H. G. |
| Article Title: | NRF2 activation confers resistance to eIF4A inhibitors in cancer therapy |
| Abstract: | Inhibition of the eIF4A RNA helicase with silvestrol and related compounds is emerging as a powerful anti-cancer strategy. We find that a synthetic silvestrol analogue (CR-1-31 B) has nanomolar activity across many cancer cell lines. It is especially active against aggressive MYC+/BCL2+ B cell lymphomas and this likely reflects the eIF4A-dependent translation of both MYC and BCL2. We performed a genome-wide CRISPR/Cas9 screen and identified mechanisms of resistance to this new class of therapeutics. We identify three negative NRF2 regulators (KEAP1, CUL3, CAND1) whose inactivation is sufficient to cause CR1-31-B resistance. NRF2 is known to alter the oxidation state of translation factors and cause a broad increase in protein production. We find that NRF2 activation particularly increases the translation of some eIF4A-dependent mRNAs and restores MYC and BCL2 production. We know that NRF2 functions depend on removal of sugar adducts by the frutosamine-3-kinase (FN3K). Accordingly, loss of FN3K results in NRF2 hyper-glycation and inactivation and resensitizes cancer cells to eIF4A inhibition. Together, our findings implicate NRF2 in the translation of eIF4A-dependent mRNAs and point to FN3K inhibition as a new strategy to block NRF2 functions in cancer. © 2021 by the authors. Licensee MDPI, Basel, Switzerland. |
| Keywords: | drug resistance; lymphoma; g-quadruplex; silvestrol; nrf2; eif4a; keap1 |
| Journal Title: | Cancers |
| Volume: | 13 |
| Issue: | 4 |
| ISSN: | 2072-6694 |
| Publisher: | MDPI |
| Date Published: | 2021-02-01 |
| Start Page: | 639 |
| Language: | English |
| DOI: | 10.3390/cancers13040639 |
| PROVIDER: | scopus |
| PMCID: | PMC7915661 |
| PUBMED: | 33562682 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 March 2021 -- Source: Scopus |
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