NRF2-Dependent Bioactivation of Mitomycin C as a Novel Strategy To Target KEAP1-NRF2 Pathway Activation in Human Cancer

ABSTRACT

Activating mutations in the KEAP1-NRF2 pathway are found in approximately 25% of lung tumors, where the hijacking of NRF2’s cytoprotective functions results in aggressive tumor growth, chemoresistance, and a poor prognosis for patients. There are currently no approved drugs which target aberrant NRF2 activation, which means that there is an urgent clinical need to target this orphan oncogenic pathway in human tumors. In this study, we used an isogenic pair of wild-type and Keap1 knockout cells to screen a range of chemotherapeutic and pathway-targeted anticancer drugs in order to identify compounds which display enhanced toxicity toward cells with high levels of Nrf2 activity. Through this approach, complemented by validation across a panel of eight human cancer cell lines from a range of different tissues, we identified the DNA-damaging agent mitomycin C to be significantly more toxic in cells with aberrant Nrf2 activation. Mechanistically, we found that the NRF2 target genes for cytochrome P450 reductase, NQO1, and enzymes in the pentose phosphate pathway are all responsible for the NRF2-dependent enhanced bioactivation of mitomycin C. As mitomycin C is already approved for clinical use, it represents as excellent drug repositioning candidate to target the currently untreatable NRF2 activation in human tumors.

KEYWORDS:

• NRF2
• KEAP1
• NFE2L2
• oxidative stress
• cancer
• drug repositioning
• concurrent synthetic lethality

ACKNOWLEDGMENTS

We thank all of the members of the Yamamoto lab for their thoughtful and stimulating discussions.

This research was partially supported by the Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research [BINDS]) from AMED under grant number JP17am0101001 (support number 1234), AMED-P-CREATE (JP19cm0106101 to M.Y.), JSPS KAKENHI 19H05649 (to M.Y.), and JSPS KAKENHI Grants-in-Aid for Early Career Scientists 19K16512 (to L.B.).