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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.
AuthorsJennifer A Seamon, Catherine A Rugg, Stuart Emanuel, Anna Maria Calcagno, Suresh V Ambudkar, Steven A Middleton, Jeannene Butler, Virna Borowski, Lee M Greenberger
JournalMolecular cancer therapeutics (Mol Cancer Ther) Vol. 5 Issue 10 Pg. 2459-67 (Oct 2006) ISSN: 1535-7163 [Print] United States
PMID17041089 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
Chemical References
  • ABCG2 protein, human
  • Abcg2 protein, mouse
  • Antineoplastic Agents
  • Enzyme Inhibitors
  • JNJ-7706621
  • Neoplasm Proteins
  • Triazoles
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases
  • Cyclin-Dependent Kinases
Topics
  • ATP-Binding Cassette Transporters (biosynthesis, genetics, physiology)
  • Administration, Oral
  • Animals
  • Antineoplastic Agents (pharmacokinetics, pharmacology)
  • Aurora Kinases
  • Biological Availability
  • Cyclin-Dependent Kinases (antagonists & inhibitors)
  • Drug Resistance, Neoplasm
  • Enzyme Inhibitors (pharmacology)
  • HeLa Cells
  • Humans
  • Mice
  • Mice, Knockout
  • Neoplasm Proteins (biosynthesis, physiology)
  • Protein-Serine-Threonine Kinases (antagonists & inhibitors)
  • Triazoles (pharmacokinetics, pharmacology)

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