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The efflux pump ABCC1/MRP1 constitutively restricts PROTAC sensitivity in cancer cells
Gernot Wolf1, Conner Craigon2, Shao Thing Teoh1
1CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria.
Cell Chemical Biology
|January 4, 2025
Summary
Cellular transporters limit proteolysis targeting chimera (PROTAC) effectiveness. Researchers identified ABCC1/MRP1 as a key factor in PROTAC resistance, crucial for overcoming drug limitations in cancer therapy.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Proteolysis targeting chimeras (PROTACs) are bifunctional molecules enabling targeted protein degradation.
- PROTACs offer potential for targeting previously undruggable proteins, with several candidates in clinical trials.
- The role of cellular transporters in PROTAC pharmacokinetics is largely unknown.
Purpose of the Study:
- To investigate the role of cellular transmembrane transporters in PROTAC uptake and efflux.
- To identify genetic factors contributing to PROTAC resistance.
Main Methods:
- Utilized transporter-focused genetic screens to identify PROTAC resistance factors.
- Conducted genome-wide PROTAC resistance screens.
Main Results:
- Identified ATP-binding cassette transporter ABCC1/MRP1 as a significant PROTAC resistance factor.
- ABCC1 is constitutively expressed in various cancers, limiting PROTAC bioavailability.
- Identified ubiquitination, mTOR signaling, and apoptosis pathways as involved in PROTAC resistance.
Conclusions:
- ABCC1 acts as a crucial efflux pump limiting PROTAC efficacy in cancer cells.
- Findings provide insights into overcoming PROTAC resistance for improved cancer therapy.
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