Nearly 80% of children with ALL are cured following chemotherapeutic treatment. However, the remaining 20% often exhibit drug resistance and treatment failure that is poorly understood. In some cases, patients are resistant to multiple drugs that have very little structural similarity, suggesting that the mechanisms for drug cross-resistance are probably not the same as mechanisms underlying resistance to a single drug. Dr. William E. Evans from St. Jude Children's Research Hospital and colleagues used a comprehensive genetic screening technique to search for genes that are differentially expressed in ALL cells that demonstrated cross-resistance to two or more commonly used chemotherapeutic agents.
The researchers identified several genes that were differentially expressed in ALL cells that exhibited de novo cross resistance to four widely used antileukemic agents. They went on to investigate the relationship of these genes to treatment outcome in ALL patients and found that expression of the genes was associated with treatment outcome and could be used to identify a subset of patients with a markedly inferior response to treatment. In addition, the findings revealed a previously unrecognized phenotype characterized by discordant resistance to two widely used and mechanistically distinct antileukemic agents and provided new information about the cellular mechanisms involved in disparate response to these drugs.
Specific genetic signatures related to ALL treatment failure and chemotherapeutic cross-resistance were more effective at identifying select populations of patients with inferior treatment outcomes than expression patterns associated with resistance to a single drug. "These findings provide new insights into the biological basis of de novo multiple-drug resistance and illuminate potential new targets for overcoming this cause of treatment failure in childhood ALL," explains Dr. Evans.
The researchers included Sanne Lugthart from St. Jude Children's Research Hospital and Erasmus University Medical Center/Sophia Children's Hospital, Rotterdam; Meyling H. Cheok and Cheng Cheng from St. Jude Children's Research Hospital; Monique L. den Boer and Amy Holleman from Erasmus University Medical Center/Sophia Children's Hospital, Rotterdam; Wenjian Yang, Ching-Hon Pui, Mary V. Relling, and William E. Evans from St. Jude Children's Research Hospital and Pharmacogenetics Research Network, Memphis; Gritta E. Janka-Schaub from Children's University Hospital, Hamburg; and Rob Pieters from Erasmus University Medical Center/Sophia Children's Hospital, Rotterdam. This work was supported in part by the following grants: the Junior research fellowship of the Sophia Children's Hospital Foundation and the Dutch Cancer Foundation 2003, the Netherlands; the Pediatric Oncology Foundation and the Nijbakker-Morra Foundation, the Netherlands; the Renee Vogel Stipendium 2002, the Netherlands; the National Institutes of Health; the National Institutes of Health; the National Institutes of Health, and the American Lebanese Syrian Associated Charities; Cancer Center Support Grant and the American Cancer Society and F.M. Kirby Clinical Research Professorship.
Publishing in Cancer Cell, Volume 7, Number 4, April 2005, pages 375-386. http://www.cancercell.org
Journal
Cancer Cell