A novel small molecule RAD51 inactivator overcomes imatinib-resistance in chronic myeloid leukaemia

Jiewen Zhu, Longen Zhou, Guikai Wu, Heiko Konig, Xiaoqin Lin, Guideng Li, Xiao Long Qiu, Chi Fen Chen, Chun Mei Hu, Erin Goldblatt, Ravi Bhatia, A. Richard Chamberlin, Phang Lang Chen, Wen Hwa Lee

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

RAD51 recombinase activity plays a critical role for cancer cell proliferation and survival, and often contributes to drug-resistance. Abnormally elevated RAD51 function and hyperactive homologous recombination (HR) rates have been found in a panel of cancers, including breast cancer and chronic myeloid leukaemia (CML). Directly targeting RAD51 and attenuating the deregulated RAD51 activity has therefore been proposed as an alternative and supplementary strategy for cancer treatment. Here we show that a newly identified small molecule, IBR2, disrupts RAD51 multimerization, accelerates proteasome-mediated RAD51 protein degradation, reduces ionizing radiation-induced RAD51 foci formation, impairs HR, inhibits cancer cell growth and induces apoptosis. In a murine imatinib-resistant CML model bearing the T315I Bcr-abl mutation, IBR2, but not imatinib, significantly prolonged animal survival. Moreover, IBR2 effectively inhibits the proliferation of CD34+ progenitor cells from CML patients resistant to known BCR-ABL inhibitors. Therefore, small molecule inhibitors of RAD51 may suggest a novel class of broad-spectrum therapeutics for difficult-to-treat cancers. A newly identified RAD51 inhibitor leading to degradation of RAD51 via the proteasome pathway inhibits cancer cell survival and greatly increases life spans in a mouse chronic myeloid leukaemia model.

Original languageEnglish (US)
Pages (from-to)353-365
Number of pages13
JournalEMBO Molecular Medicine
Volume5
Issue number3
DOIs
StatePublished - Mar 1 2013

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Keywords

  • CML
  • Cancer
  • Inhibitor
  • RAD51
  • Small molecule

ASJC Scopus subject areas

  • Molecular Medicine

Cite this

Zhu, J., Zhou, L., Wu, G., Konig, H., Lin, X., Li, G., Qiu, X. L., Chen, C. F., Hu, C. M., Goldblatt, E., Bhatia, R., Chamberlin, A. R., Chen, P. L., & Lee, W. H. (2013). A novel small molecule RAD51 inactivator overcomes imatinib-resistance in chronic myeloid leukaemia. EMBO Molecular Medicine, 5(3), 353-365. https://doi.org/10.1002/emmm.201201760