title: Role of the ABCG2 drug transporter in the resistance and oral bioavailability of a potent cyclin-dependent kinase/Aurora kinase inhibitor.
abstract: Cell cycle kinase inhibitors have advanced into clinical trials in oncology. One such molecule, JNJ-7706621, is a broad-spectrum inhibitor of the cyclin-dependent kinases and Aurora kinases that mediate G(2)-M arrest and inhibits tumor growth in xenograft models. To determine the putative mechanisms of resistance to JNJ-7706621 that might be encountered in the clinic, the human epithelial cervical carcinoma cell line (HeLa) was exposed to incrementally increasing concentrations of JNJ-7706621. The resulting resistant cell population, designated HeLa-6621, was 16-fold resistant to JNJ-7706621, cross-resistant to mitoxantrone (15-fold) and topotecan (6-fold), and exhibited reduced intracellular drug accumulation of JNJ-7706621. ABCG2 was highly overexpressed at both the mRNA ( approximately 163-fold) and protein levels. The functional role of ABCG2 in mediating resistance to JNJ-7706621 was consistent with the following findings: (a) an ABCG2 inhibitor, fumitremorgin C, restored the sensitivity of HeLa-6621 cells to JNJ-7706621 and to mitoxantrone; (b) human embryonic kidney-293 cells transfected with ABCG2 were resistant to both JNJ-7706621 and mitoxantrone; and (c) resistant cells that were removed from the drug for 12 weeks and reverted to susceptibility to JNJ-7706621 showed near-normal ABCG2 RNA levels. ABCG2 is likely to limit the bioavailability of JNJ-7706621 because oral administration of JNJ-7706621 to Bcrp (the murine homologue of ABCG2) knockout mice resulted in an increase in the plasma concentration of JNJ-7706621 compared with wild-type mice. These findings indicate that ABCG2 mediates the resistance to JNJ-7706621 and alters the absorption of the compound following administration.
authors.affiliation: Cancer Therapeutics Research, Johnson & Johnson Pharmaceutical Research and Development, LLC, Raritan, NJ 08560, USA. jseamon@prdus.jnj.com
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Seamon
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Rugg
authors.forename: Stuart
authors.initials: S
authors.lastname: Emanuel
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Calcagno
authors.forename: Suresh V
authors.initials: SV
authors.lastname: Ambudkar
authors.forename: Steven A
authors.initials: SA
authors.lastname: Middleton
authors.forename: Jeannene
authors.initials: J
authors.lastname: Butler
authors.forename: Virna
authors.initials: V
authors.lastname: Borowski
authors.forename: Lee M
authors.initials: LM
authors.lastname: Greenberger
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology*; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D064127:Aurora Kinases; D001682:Biological Availability; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D014230:Triazoles / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C506121:JNJ-7706621; D009363:Neoplasm Proteins; D014230:Triazoles; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D018844:Cyclin-Dependent Kinases