A Small Molecule Inhibits Deregulated NRF2 Transcriptional
Activity in Cancer
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Abstract
NRF2
serves as the master regulator of oxidative stress resistance
in mammalian cells. Although NRF2 activation decreases tumorigenic
events in normal cells, accumulating evidence suggests that cancers
have broadly selected for NRF2-activating mutations to promote anabolic
growth and chemoresistance. Small molecules which inhibit NRF2 activity
may therefore offer promise as an alternative anticancer treatment
in NRF2 dependent cancers. We have used a high throughput screen to
identify small molecules which decrease NRF2 transcriptional activity
at antioxidant response element sites. One such molecule, termed AEM1,
is capable of broadly decreasing the expression of NRF2 controlled
genes, sensitizing A549 cells to various chemotherapeutic agents,
and inhibiting the growth of A549 cells <i>in vitro</i> and <i>in vivo</i>. Profiling of multiple cell lines for their responsiveness
to AEM1 revealed that AEM1’s activities are restricted to cell
lines harboring mutations which render NRF2 constitutively active