Patients with chronic myelogenous leukaemia, acute lymphoblastic leukaemia and gastrointestinal tumours treated long term with imatinib (Glivec) almost always develop acquired resistance. Several mechanisms of imatinib resistance have recently been documented and now Burger and colleagues have identified yet another novel mechanism mediated by the breast cancer resistance gene BCRP .

Imatinib, a tyrosine-kinase inhibitor effective against BCR-ABL1, KIT and platelet-derived growth factor receptor, is an orally administered drug. Given that BCRP is highly expressed within the gastrointestinal tract and is a member of the ABC family of drug transporters, it seems likely that BCRP is involved in limiting the uptake of imatinib into the blood, thereby limiting the biological availability of imatinib. So, Burger et al. asked if imatinib is a substrate of BCRP. Initially, the authors used two breast cancer cell sublines that overexpressed either wild-type (Arg482) or mutant (Thr482) BCRP, a mutation previously shown to affect substrate specificity. Carbon-14 labelled imatinib was used to measure drug uptake. Both wild-type overexpressing cells and mutant-BCRP expressing cells had significantly less drug accumulation than controls, indicating that both the mutant and wild-type BCRP proteins act as drug-efflux pumps for imatinib. Real-time PCR analyses and western-blot data confirmed that other ABC drug-efflux proteins — MDR1, MRP1 and MRP2 – were not overexpressed in these cells.

To further examine this interaction, the authors monitored the efflux of imatinib and three other known BCRP substrates: mitoxantrone, and methotrexate and doxorubicin, two substrates that are exclusive targets for wild-type or mutant BCRP, respectively. Imatinib is exported in a similar manner to mitoxantrone by both wild-type and mutant-BCRP expressing cells. In addition, efflux of imatinib was reduced in the presence of a BCRP-specific inhibitor, further demonstrating that imatinib is a bona fide substrate for BCRP.

The similar efflux profiles of imatinib and mitoxantrone indicated that imatinib might be a competitive substrate. Indeed, the authors show that imatinib inhibits the efflux of mitroxantrone, indicating that combined treatment with imatinib and another BCRP substrate might improve the biological availability of these drugs and/or increase the side effects due to increased cellular accumulation.

Burger and colleagues conclude that BCRP is likely to be involved in the resistance mechanisms seen in patients on long-term imatinib and indicate that future regimens for combined drug-treatment programmes should target multiple drug-resistance pathways.