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A forward genetic screen identifies modifiers of rocaglate responsiveness
Leo Shen1, Lauren Pugsley1, Regina Cencic1
1Department of Biochemistry, McGill University, Montreal, QC, H3G 1Y6, Canada.
Scientific Reports
|September 17, 2021
Summary
Rocaglates are chemotherapy drugs targeting translation initiation factor 4A. We identified FOXP3 and NR1I3 as key factors conferring resistance, mediated by P-glycoprotein, suggesting combination therapies.
Area of Science:
- Molecular Biology
- Oncology
- Pharmacology
Background:
- Rocaglates are novel chemotherapy agents targeting eukaryotic initiation factor (eIF) 4A, crucial for protein translation.
- Understanding resistance mechanisms is vital for clinical application of rocaglates.
Purpose of the Study:
- To identify genetic factors conferring resistance to rocaglates.
- To explore potential therapeutic strategies to overcome rocaglate resistance.
Main Methods:
- Utilized a positive selection, ORFeome screen to identify resistance-conferring cDNAs.
- Investigated the role of identified factors (FOXP3, NR1I3) in rocaglate response and P-glycoprotein (Pgp) regulation.
Main Results:
- FOXP3 and NR1I3 were identified as potent modifiers of rocaglate response.
- These transcription factors regulate ABCB1, the gene encoding P-glycoprotein (Pgp).
- FOXP3 and NR1I3 induced a multi-drug resistant phenotype reversed by Pgp inhibition.
Conclusions:
- FOXP3 and NR1I3 contribute to rocaglate resistance through Pgp.
- Inhibition of Pgp may overcome rocaglate resistance, suggesting combination therapy potential.
