2020 Fiscal Year Annual Research Report
Development of an Nrf2 inhibitor for the treatment of Nrf2-addicted cancer
| Project/Area Number |
19K16512
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| Research Institution | Tohoku University |
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Principal Investigator |
Baird Liam 東北大学, 医学系研究科, 助教 (90724914)
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| Project Period (FY) |
2019-04-01 – 2021-03-31
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| Keywords | Keap1-Nrf2 / synthetic lethal |
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| Outline of Annual Research Achievements |
In order to selectively target tumours with aberrant NRF2 activity, we developed a novel synthetic lethal screening strategy utilizing an isogenic pair of fluorescently labelled cell lines for use in the identification of novel anti-cancer drugs. We have characterized these cells to show that they accurately model NRF2 activation in cancer, and are thus well suited for use in screening. Using this system, we identified the family of HSP90 inhibitors based on the geldanamycin scaffold to be synthetic lethal with NRF2 activity. Mechanistically, we found that the NRF2 target gene NQO1 is able to metabolize the quinone ring in these compounds into a more potent hydroquinone form, which specifically induces cell death in cells with high levels of NRF2 activity. We validated this result using pairs of WT and NRF2 active human cancer cell lines derived from lung, oesophagus and liver tumours, and found that in all cases, the geldanamycin-derived HSP90 inhibitors were able to kill the cells in an NRF2-dependent manner. For in vivo validation, we used a xenotransplant system from which we found that the HSP90 inhibitor 17-AAG could significant reduce the size of Keap1 KO derived tumours in mice.
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