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Research Article | Spotlight

Geldanamycin-Derived HSP90 Inhibitors Are Synthetic Lethal with NRF2

Liam Baird, Takafumi Suzuki, Yushi Takahashi, Eiji Hishinuma, Daisuke Saigusa, Masayuki Yamamoto
Liam Baird
aDepartment of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
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Takafumi Suzuki
aDepartment of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
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Yushi Takahashi
aDepartment of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
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Eiji Hishinuma
bTohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
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Daisuke Saigusa
aDepartment of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
bTohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
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Masayuki Yamamoto
aDepartment of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
bTohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
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  • ORCID record for Masayuki Yamamoto
DOI: 10.1128/MCB.00377-20
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ABSTRACT

Activating mutations in KEAP1-NRF2 are frequently found in tumors of the lung, esophagus, and liver, where they are associated with aggressive growth, resistance to cancer therapies, and low overall survival. Despite the fact that NRF2 is a validated driver of tumorigenesis and chemotherapeutic resistance, there are currently no approved drugs which can inhibit its activity. Therefore, there is an urgent clinical need to identify NRF2-selective cancer therapies. To this end, we developed a novel synthetic lethal assay, based on fluorescently labeled isogenic wild-type and Keap1 knockout cell lines, in order to screen for compounds which selectively kill cells in an NRF2-dependent manner. Through this approach, we identified three compounds based on the geldanamycin scaffold which display synthetic lethality with NRF2. Mechanistically, we show that products of NRF2 target genes metabolize the quinone-containing geldanamycin compounds into more potent HSP90 inhibitors, which enhances their cytotoxicity while simultaneously restricting the synthetic lethal effect to cells with aberrant NRF2 activity. As all three of the geldanamycin-derived compounds have been used in clinical trials, they represent ideal candidates for drug repositioning to target the currently untreatable NRF2 activity in cancer.

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Geldanamycin-Derived HSP90 Inhibitors Are Synthetic Lethal with NRF2
Liam Baird, Takafumi Suzuki, Yushi Takahashi, Eiji Hishinuma, Daisuke Saigusa, Masayuki Yamamoto
Molecular and Cellular Biology Oct 2020, 40 (22) e00377-20; DOI: 10.1128/MCB.00377-20

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Geldanamycin-Derived HSP90 Inhibitors Are Synthetic Lethal with NRF2
Liam Baird, Takafumi Suzuki, Yushi Takahashi, Eiji Hishinuma, Daisuke Saigusa, Masayuki Yamamoto
Molecular and Cellular Biology Oct 2020, 40 (22) e00377-20; DOI: 10.1128/MCB.00377-20
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KEYWORDS

NRF2
KEAP1
oxidative stress
cancer
synthetic lethal
NFE2L2

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