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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. Strategies to circumvent the reduced drug accumulation conferred by these polyspecific efflux transporters have relied on attempts to develop drugs that bypass extrusion (often with a sacrifice in activity) or the exploration of clinical inhibitors that, although showing promise in vitro, have not translated to the clinic. Alterations that confer selective advantage during the evolution of cancer cells might also create vulnerabilities that can be exploited therapeutically. 1 As defined by Szybalski and Bryson, collateral sensitivity is a “phenomenon in drug-resistant cells (prokaryotic or eukaryotic) identified during most in vitro studies...[whereby] the development of resistance in cells to one agent can confer higher sensitivity to an …