Nrf2 activation confers resistance to eif4a inhibitors in cancer therapy

Viraj R. Sanghvi, Prathibha Mohan, Kamini Singh, Linlin Cao, Marjan Berishaj, Andrew L. Wolfe, Jonathan H. Schatz, Nathalie Lailler, Elisa de Stanchina, Agnes Viale, Hans Guido Wendel

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number639
Pages (from-to)1-13
Number of pages13
JournalCancers
Volume13
Issue number4
DOIs
StatePublished - Feb 2 2021

Keywords

  • Drug resistance
  • EIF4A
  • G-quadruplex
  • KEAP1
  • Lymphoma
  • NRF2
  • Silvestrol

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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