Bosutinib resistance linked to ABCB1 transporter

Jul 24 2015

By Lynda Williams, Senior medwireNews Reporter

Resistance to the tyrosine kinase inhibitor (TKI) bosutinib may be mediated by overexpression of the efflux transporter ABCB1, scientists suggest .

The team reports the results of in vitro analysis of three well known drug transporters associated with TKI resistance in chronic myeloid leukaemia (CML) – ABCB1, ABCG2 and SLC22A1.

Cells overexpressing ABCG2 or SLC22A1 did not show any difference in the uptake of radiolabelled bosutinib, say Sara Radaelli, from University of Milano-Bicocca in Monza, Italy, and co-workers.

By contrast, cells overexpressing ABCB1 had a significant decrease in bosutinib incorporation, indicating that this transporter regulates intracellular bosutinib levels.

The half maximal inhibitory concentration (IC50) for bosutinib was significantly reduced in cells overexpressing ABCB1 when they were exposed to the ABCB1 inhibitor verapamil; by contrast, the IC50 of cells with regular ABCB1 expression was not affected by the presence of verapamil.

“These results indicate that ABCB1 overexpression decreases sensitivity to bosutinib, and inhibition of ABCB1 restores sensitivity to bosutinib in cells overexpressing ABCB1”, the researchers explain in the Journal of Hematology & Oncology.

In vivo research in mice confirmed these findings, showing that mice with tumours overexpressing ABCB1 had a “limited” response to bosutinib and experienced relapse after treatment ended, whereas animals with tumours expressing normal levels of ABCB1 were completely sensitive to the TKI and had sustained regression after treatment discontinued.

“[W]e show here that intracellular concentrations of bosutinib are affected by the overexpression of the efflux transporter ABCB1”, the team summarises.

“The reduced intracellular bosutinib concentration results in a reduction of its BCR-ABL inhibitory activity, thus leading to resistance.”

The researchers hypothesise their findings could be useful in the clinical management of Philadelphia chromosome-positive leukaemia.

“Further studies should be carried out in BCR-ABL+ patients under treatment with bosutinib to reveal any correlation between ABCB1 activity and clinical response which might allow the development of strategies to overcome bosutinib resistance”, they recommend.

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