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Research Articles: Therapeutics, Targets, and Development

Role of the ABCG2 drug transporter in the resistance and oral bioavailability of a potent cyclin-dependent kinase/Aurora kinase inhibitor

¹ Cancer Therapeutics Research, Johnson & Johnson Pharmaceutical Research and Development, LLC, Raritan, New Jersey and ² The Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Department of Health and Human Services, Bethesda, Maryland

Requests for reprints: Jennifer Seamon, Johnson & Johnson Pharmaceutical Research and Development, LLC, 1125 Trenton-Harbourton Road, P.O. Box 200, Titusville, NJ 08560. Phone: 609-730-3569; Fax: 609-730-2061. E-mail: jseamon{at}prdus.jnj.com

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 G₂-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 (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. [Mol Cancer Ther 2006;5(10):2459–67]

Grant support: A.M. Calcagno was supported by the National Institute of General Medical Sciences Pharmacology Research Associate Program, the research work of A.M. Calcagno and S.V. Ambudkar was supported by the Intramural Research Program of the National Cancer Institute, NIH.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: Current address for J.A. Seamon, Medical Knowledge Management, Johnson & Johnson Pharmaceutical Research and Development, LLC, Titusville, NJ 08560.

Present address for C.A. Rugg: Screening and Assay Sciences, Lead Identification Technology, Sanofi-Aventis Bridgewater, NJ 08807.

Present address for S. Emanuel, Oncology, Drug Discovery, Bristol-Myers Squibb Company, Princeton, NJ 08543.

Present address for S.A. Middleton: PDME Early Strategic Planning, Hoffmann-La Roche Inc., Nutley, NJ 07110.

Present address for V. Borowski: PRI-Discovery Immunology, Bristol-Myers Squibb Company, Princeton, NJ 08543.

Present address for L.M. Greenberger: Enzon Pharmaceuticals, Inc., Piscataway, NJ 08854.

Received 6/ 7/06; revised 8/ 3/06; accepted 8/25/06.