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Multiple drug resistance (MDR) is a prominent way by which cancer develops resistance to various chemotherapeutic agents and continues to be a hurdle in treating cancer patients. A few ATP binding cassette (ABC) transporters have been described as comprising the main mechanism behind MDR: ABCB1, ABCC1, and ABCG2. Of these three, ABCG2 is unique in that it seems to be mainly expressed in solid tumors. Despite the recent discovery of many compounds that inhibit its activity, it remains one of the least well-studied transporters in both animal models and in humans with regard to its contribution to MDR. Though the blockade of the ABCG2 efflux protein has great potential in reversing MDR in cancer, will it be enough to overcome chemoresistance in the clinic?