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Published on: May 27, 2021
Geldanamycin-Derived HSP90 Inhibitors Are Synthetic Lethal with NRF2
Liam Baird1, Takafumi Suzuki2, Yushi Takahashi2
1Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan liambaird@med.tohoku.ac.jp masiyamamoto@med.tohoku.ac.jp.
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.
Insights
Targeting KEAP1-NRF2 mutations in cancer is crucial. Researchers found geldanamycin derivatives selectively kill cancer cells with NRF2 alterations by enhancing HSP90 inhibition, offering new therapeutic strategies.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Activating mutations in KEAP1-NRF2 are common in lung, esophageal, and liver cancers.
- These mutations drive tumor growth, therapy resistance, and poor survival.
- NRF2 is a key driver of tumorigenesis and chemoresistance, yet lacks targeted inhibitors.
Purpose of the Study:
- To identify novel cancer therapies that selectively target NRF2 activity.
- To develop a synthetic lethal assay for screening NRF2-dependent compounds.
- To explore drug repositioning opportunities for existing compounds.
Main Methods:
- Developed a novel synthetic lethal assay using isogenic wild-type and Keap1 knockout cell lines.
- Screened compounds for selective killing of cells with NRF2-dependent activity.
- Investigated the mechanism of action for identified compounds.
Main Results:
- Identified three geldanamycin scaffold compounds exhibiting synthetic lethality with NRF2.
- Demonstrated that NRF2 target genes metabolize geldanamycin into more potent HSP90 inhibitors.
- Showed enhanced cytotoxicity specifically in cancer cells with aberrant NRF2 activity.
Conclusions:
- Geldanamycin derivatives represent promising candidates for NRF2-selective cancer therapy.
- Drug repositioning of these clinically tested compounds offers a viable strategy.
- This approach targets currently untreatable NRF2-driven cancers.
