Targeting the achilles heel of multidrug-resistant cancer by exploiting the fitness cost of resistance

Gergely Szakács, Matthew D. Hall, Michael M. Gottesman, Ahcène Boumendjel, Remy Kachadourian, Brian J. Day, Hélène Baubichon-Cortay, Attilio Di Pietro

Research output: Contribution to journalReview article

112 Citations (Scopus)

Abstract

The development of multidrug resistance (MDR) in patients suffering cancer remains a significant clinical challenge, with drug efflux by ABC (ATP-binding cassette) transporters contributing significantly. Theoretically, one could restore the efficacy of first-line drugs by circumventing these resistance mechanisms. However, cancer is a heterogeneous disease that can exhibit different characteristics from patient to patient or even within a single patient. Spatial and temporal heterogeneity is a result of continuous adaptation to selective pressures through sequential genetic changes that ultimately convert a normal cell into intractable cancer. Thus, cancer cells are moving targets, as individual cells in a tumor mass constantly adapt to local environmental challenges. Biological membranes represent a significant permeation barrier and thus play a critical role in the protection of pharmacokinetic compartments. Conversely, the activity of a drug ultimately depends on the ability of the compound to reach its target, which might reside in a well-protected pharmacological sanctuary.

Original languageEnglish
Pages (from-to)5753-5774
Number of pages22
JournalChemical reviews
Volume114
Issue number11
DOIs
Publication statusPublished - Jun 11 2014

ASJC Scopus subject areas

  • Chemistry(all)

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    Szakács, G., Hall, M. D., Gottesman, M. M., Boumendjel, A., Kachadourian, R., Day, B. J., Baubichon-Cortay, H., & Di Pietro, A. (2014). Targeting the achilles heel of multidrug-resistant cancer by exploiting the fitness cost of resistance. Chemical reviews, 114(11), 5753-5774. https://doi.org/10.1021/cr4006236