@article{e269564a1cc4479cbf3966c1107607a2,
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.",
keywords = "Drug resistance, EIF4A, G-quadruplex, KEAP1, Lymphoma, NRF2, Silvestrol",
author = "Sanghvi, {Viraj R.} and Prathibha Mohan and Kamini Singh and Linlin Cao and Marjan Berishaj and Wolfe, {Andrew L.} and Schatz, {Jonathan H.} and Nathalie Lailler and {de Stanchina}, Elisa and Agnes Viale and Wendel, {Hans Guido}",
note = "Funding Information: V.R.S. is a recipient of the DoD Concept Award and Rally Foundation Young Investigator Award. E.d.S. is supported by MSKCC core grant P30 CA008748 and NIH U54 OD020355?01. H.-G.W. is supported by the Lymphoma Research Foundation, William H. Goodwin and Alice Goodwin and the Commonwealth Foundation for Cancer Research; the Center for Experimental Therapeutics at MSKCC; NIH grants R01 CA183876, R01 CA248168, R01 CA207217, R35 CA252982, PA50 CA217694, and P50 CA192937; the Starr Cancer Consortium; the Geoffrey Beene Cancer Research Center; Steven A. Greenberg Start-up Grant, Cycle for Survival, a Leukemia and Lymphoma Society (LLS) SPORE grant; the MSKCC Core Grant (P30 CA008748) and is a scholar of the Leukemia Lymphoma Society. Funding Information: Funding: V.R.S. is a recipient of the DoD Concept Award and Rally Foundation Young Investigator Award. E.d.S. is supported by MSKCC core grant P30 CA008748 and NIH U54 OD020355–01. H.-G.W. is supported by the Lymphoma Research Foundation, William H. Goodwin and Alice Goodwin and the Commonwealth Foundation for Cancer Research; the Center for Experimental Therapeutics at MSKCC; NIH grants R01 CA183876, R01 CA248168, R01 CA207217, R35 CA252982, PA50 CA217694, and P50 CA192937; the Starr Cancer Consortium; the Geoffrey Beene Cancer Research Center; Steven A. Greenberg Start-up Grant, Cycle for Survival, a Leukemia and Lymphoma Society (LLS) SPORE grant; the MSKCC Core Grant (P30 CA008748) and is a scholar of the Leukemia Lymphoma Society. Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland.",
year = "2021",
month = feb,
day = "2",
doi = "10.3390/cancers13040639",
language = "English (US)",
volume = "13",
pages = "1--13",
journal = "Cancers",
issn = "2072-6694",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "4",
}