Drug efflux by breast cancer resistance protein is a mechanism of resistance to the benzimidazole insulin-like growth factor receptor/insulin receptor inhibitor, BMS-536924.

Publication Type:

Journal Article

Source:

Molecular cancer therapeutics, Volume 10, Issue 1, p.117-25 (2011)

Keywords:

ATP-Binding Cassette Transportersdigestive disease, digestive deseases Benzimidazolesdigestive disease, digestive deseases Breast Neoplasmsdigestive disease, digestive deseases Cell Growth Processesdigestive disease, digestive deseases Cell Line, Tumordigestive disease, digestive deseases Drug Resistance, Neoplasmdigestive disease, digestive deseases Femaledigestive disease, digestive deseases Humansdigestive disease, digestive deseases Neoplasm Proteinsdigestive disease, digestive deseases Pyridonesdigestive disease, digestive deseases Receptor, IGF Type 1digestive disease, digestive deseases Receptors, Somatomedindigestive disease, digestive deseases Up-Regulation

Abstract:

Preclinical investigations have identified insulin-like growth factor (IGF) signaling as a key mechanism for cancer growth and resistance to clinically useful therapies in multiple tumor types including breast cancer. Thus, agents targeting and blocking IGF signaling have promise in the treatment of solid tumors. To identify possible mechanisms of resistance to blocking the IGF pathway, we generated a cell line that was resistant to the IGF-1R/InsR benzimidazole inhibitors, BMS-554417 and BMS-536924, and compared expression profiles of the parental and resistant cells lines using Affymetrix GeneChip Human Genome U133 arrays. Compared with MCF-7 cells, breast cancer resistance protein (BCRP) expression was increased 9-fold in MCF-7R4, which was confirmed by immunoblotting and was highly statistically significant (P = 7.13E-09). BCRP was also upregulated in an independently derived resistant cell line, MCF-7 924R. MCF-7R4 cells had significantly lower intracellular accumulation of BMS-536924 compared with MCF-7 cells. Expression of BCRP in MCF-7 cells was sufficient to reduce sensitivity to BMS-536924. Furthermore, knockdown of BCRP in MCF-7R4 cells resensitized cells to BMS-536924. Four cell lines selected for resistance to the pyrrolotriazine IGF-1R/InsR inhibitor, BMS-754807, did not have upregulation of BCRP. These data suggest that benzimidazole IGF-1R/InsR inhibitors may select for upregulation and be effluxed by the ATP-binding cassette transporter, BCRP, contributing to resistance. However, pyrrolotriazine IGF-1R/InsR inhibitors do not appear to be affected by this resistance mechanism.