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
Notes: Article -- Export Date: 1 March 2021 -- Source: Scopus
Citation Impact
MSK Authors
  1. Agnes Viale
    231 Viale
  2. Hans Guido Wendel
    79 Wendel
  3. Jonathan Harry Schatz
    15 Schatz
  4. Viraj Sanghvi
    10 Sanghvi
  5. Andrew Lerner Wolfe
    12 Wolfe
  6. Nathalie Josette Lailler
    10 Lailler
  7. Prathibha Mohan
    11 Mohan
  8. Linlin Cao
    1 Cao