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Updated: Jun 5, 2026
High-Throughput Expression and Purification of Human Solute Carriers for Structural and Biochemical Studies
Published on: September 29, 2023
ABC transporters: unvalidated therapeutic targets in cancer and the CNS
Robert W Robey1, Paul R Massey, Laleh Amiri-Kordestani
1Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Abstract:
The discovery of the multidrug transporter P-glycoprotein (Pgp) over 35 years ago in drug resistant cells prompted several decades of work attempting to overcome drug resistance by inhibition of drug efflux. Despite convincing laboratory data showing that drug transport can be inhibited in vitro, efforts to translate this discovery to the clinic have not succeeded. Since overexpression of Pgp and related transporters including ABCG2 and members of the ABCC family have been linked with poor outcome, it remains a reasonable hypothesis that this poor outcome is linked to reduction of drug exposure by efflux, and thus to drug resistance. In this review, we will discuss the question of whether ABC transporters mediate drug resistance in cancer through a reduction in drug accumulation in tumors, and whether the "Pgp inhibition hypothesis" might be wrong. The hypothesis, which holds that increased chemotherapy effectiveness can be achieved by inhibiting Pgp-mediated drug efflux has only been validated in model systems. Possible explanations for the failure to validate this clinically include the existence of other modulators of drug accumulation and uptake in tumors. Despite these difficulties, a potential role has emerged for drug transporters as therapeutic targets in the central nervous system (CNS). Both lines of investigation point to the need for imaging agents to facilitate the study of drug accumulation in human cancer. This is a critical need for targeted therapies where an important dose-response relationship is likely to exist, and where drug resistance renders many of the novel targeted agents ineffective in a subset of patients.
Insights
Decades of research aimed at overcoming cancer drug resistance by inhibiting P-glycoprotein (Pgp) have yielded limited clinical success. This review questions the "Pgp inhibition hypothesis" and explores alternative explanations for drug resistance.
Area of Science:
- Molecular Biology
- Pharmacology
- Oncology
Background:
- The discovery of P-glycoprotein (Pgp) over 35 years ago initiated extensive research into overcoming multidrug resistance (MDR) in cancer.
- Overexpression of Pgp and related ATP-binding cassette (ABC) transporters (e.g., ABCG2, ABCC family) is linked to poor patient outcomes.
- The prevailing hypothesis suggests that inhibiting Pgp-mediated drug efflux could enhance chemotherapy effectiveness.
Purpose of the Study:
- To critically evaluate whether ABC transporters mediate cancer drug resistance by reducing drug accumulation in tumors.
- To reassess the validity of the 'Pgp inhibition hypothesis' in clinical settings.
- To explore alternative mechanisms contributing to drug resistance and identify new therapeutic strategies.
Main Methods:
- Review of existing laboratory and clinical data on P-glycoprotein and other ABC transporters in cancer.
- Analysis of the translational success of Pgp inhibitors from preclinical models to clinical application.
- Discussion of factors influencing drug accumulation and uptake in tumors.
Main Results:
- In vitro studies convincingly demonstrate that Pgp-mediated drug transport can be inhibited.
- Clinical translation of Pgp inhibition strategies to overcome drug resistance has largely failed.
- The 'Pgp inhibition hypothesis' has primarily been validated in model systems, not in human cancer patients.
Conclusions:
- The failure of Pgp inhibition in clinics suggests that other modulators of drug accumulation and uptake may play a more significant role in cancer drug resistance.
- Despite challenges, drug transporters represent potential therapeutic targets, particularly for central nervous system (CNS) diseases.
- Development of novel imaging agents is crucial for studying drug accumulation in human tumors and advancing targeted therapies.
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