Expression of multidrug transporter MRP4/ABCC4 is a marker of poor prognosis in neuroblastoma and confers resistance to irinotecan in vitro

• Published in: Molecular cancer therapeutics Vol. 4; no. 4; pp. 547 - 553
• Main Authors: Norris, Murray D, Smith, Janice, Tanabe, Kara, Tobin, Peter, Flemming, Claudia, Scheffer, George L, Wielinga, Peter, Cohn, Susan L, London, Wendy B, Marshall, Glenn M, Allen, John D, Haber, Michelle
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01.04.2005
• Subjects: Antineoplastic Agents, Phytogenic - pharmacology; Biological Transport; Camptothecin - analogs & derivatives; Camptothecin - pharmacology; Cell Line; Cell Line, Tumor; DNA, Complementary - metabolism; drug resistance; Drug Resistance, Neoplasm; Drug transport and metabolism; Enzyme Inhibitors - pharmacology; Gene Expression Regulation, Neoplastic; Humans; Immunoblotting; In Vitro Techniques; Irinotecan; Molecular diagnosis and prognosis; Molecular pharmacology; MRP4; Multidrug Resistance-Associated Proteins - chemistry; Multidrug Resistance-Associated Proteins - metabolism; neuroblastoma; Neuroblastoma - drug therapy; Neuroblastoma - genetics; Pediatric cancers; Polymerase Chain Reaction; Prognosis; prognostic marker; Time Factors; Topoisomerase I Inhibitors; Treatment Outcome; Tumor Cells, Cultured
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-04-0161

Members of the multidrug resistance–associated protein (MRP) family of transporters are believed to contribute to cytotoxic drug resistance and chemotherapy failure. We observed frequent MRP4 overexpression in aggressive primary neuroblastoma, a disease for which we have previously shown MRP1 to be a prognostic indicator. High MRP4 expression correlated with MYCN oncogene amplification and was significantly associated with poor clinical outcome. Although MRP4 is known to transport some nucleoside analogues, it has not previously been associated with resistance to drugs used to treat solid tumors. We now show that it mediates substantial resistance in vitro to the topoisomerase I poison irinotecan/CPT-11 and its active metabolite SN-38. These results suggest that MRP4 will be a useful prognostic marker for neuroblastoma and that clinical trials of irinotecan as a neuroblastoma treatment should monitor MRP4 expression. The same may be true for other tumor types expressing high levels of the transporter.