title: 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.
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.
authors.affiliation: Division of Medical Oncology, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN 55905, USA.
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Hou
authors.forename: Fei
authors.initials: F
authors.lastname: Huang
authors.forename: Joan M
authors.initials: JM
authors.lastname: Carboni
authors.forename: Karen
authors.initials: K
authors.lastname: Flatten
authors.forename: Yan W
authors.initials: YW
authors.lastname: Asmann
authors.forename: Cynthia
authors.initials: C
authors.lastname: Ten Eyck
authors.forename: Takeo
authors.initials: T
authors.lastname: Nakanishi
authors.forename: Jennifer D
authors.initials: JD
authors.lastname: Tibodeau
authors.forename: Douglas D
authors.initials: DD
authors.lastname: Ross
authors.forename: Marco M
authors.initials: MM
authors.lastname: Gottardis
authors.forename: Charles
authors.initials: C
authors.lastname: Erlichman
authors.forename: Scott H
authors.initials: SH
authors.lastname: Kaufmann
authors.forename: Paul
authors.initials: P
authors.lastname: Haluska
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D001562:Benzimidazoles / Q000493:pharmacokinetics* / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011728:Pyridones / Q000493:pharmacokinetics* / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D017451:Receptors, Somatomedin / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C504983:BMS 536924; D001562:Benzimidazoles; D009363:Neoplasm Proteins; D011728:Pyridones; D017451:Receptors, Somatomedin; D017526:Receptor, IGF Type 1