Related Experiment Video
Updated: Oct 12, 2025
Genome-Wide CRISPR Screen for Unveiling Radiosensitive and Radioresistant Genes
Published on: May 23, 2025
Genome-wide CRISPR-Cas9 screens identify mechanisms of BET bromodomain inhibitor sensitivity
David Estoppey1, Gabi Schutzius1, Christian Kolter1
1Novartis Institutes for Biomedical Research, Basel 4056, Switzerland.
Abstract:
BET bromodomain inhibitors hold promise as therapeutic agents in diverse indications, but their clinical progression has been challenging and none have received regulatory approval. Early clinical trials in cancer have shown heterogeneous clinical responses, development of resistance, and adverse events. Increased understanding of their mechanism(s) of action and identification of biomarkers are needed to identify appropriate indication(s) and achieve efficacious dosing. Using genome-wide CRISPR-Cas9 screens at different concentrations, we report molecular mechanisms defining cellular responses to BET inhibitors, some of which appear specific to a single compound concentration. We identify multiple transcriptional regulators and mTOR pathway members as key determinants of JQ1 sensitivity and two Ca2+/Mn2+ transporters, ATP2C1 and TMEM165, as key determinants of JQ1 resistance. Our study reveals new molecular mediators of BET bromodomain inhibitor effects, suggests the involvement of manganese, and provides a rich resource for discovery of biomarkers and targets for combination therapies.
Insights
BET bromodomain inhibitors show therapeutic promise but face clinical challenges. This study identifies key molecular mechanisms and biomarkers for BET inhibitor sensitivity and resistance, guiding future therapeutic development.
Area of Science:
- Pharmacology and Molecular Biology
- Cancer Therapeutics
- Drug Discovery
Background:
- BET bromodomain inhibitors are promising therapeutics but have faced clinical hurdles, including resistance and adverse events.
- Understanding their mechanisms of action and identifying biomarkers are crucial for optimizing clinical use and efficacy.
- Current clinical trials show heterogeneous responses, necessitating deeper mechanistic insights.
Purpose of the Study:
- To elucidate molecular mechanisms underlying cellular responses to BET inhibitors.
- To identify concentration-specific determinants of BET inhibitor sensitivity and resistance.
- To discover novel biomarkers and therapeutic targets for combination therapies involving BET inhibitors.
Main Methods:
- Genome-wide CRISPR-Cas9 screening at varying concentrations of BET inhibitors.
- Analysis of transcriptional regulators and signaling pathways involved in cellular response.
- Identification of genetic determinants of sensitivity and resistance.
Main Results:
- Identified transcriptional regulators and mTOR pathway members as key determinants of JQ1 sensitivity.
- Discovered ATP2C1 and TMEM165 (Ca2+/Mn2+ transporters) as key determinants of JQ1 resistance.
- Revealed concentration-dependent molecular mechanisms of BET inhibitor action.
Conclusions:
- Uncovered novel molecular mediators of BET bromodomain inhibitor effects, including potential roles for manganese.
- Provided a comprehensive resource for identifying biomarkers to predict patient response to BET inhibitors.
- Suggested new avenues for developing combination therapies to overcome resistance and enhance efficacy.
