Imatinib and leptomycin B are effective in overcoming imatinib-resistance due to Bcr-Abl amplification and clonal evolution but not due to Bcr-Abl kinase domain mutation.
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| Abstract |
Treatment with imatinib is very effective in Bcr-Abl positive leukemia. However, development of resistance to this drug is a common phenomenon in late stage disease. The Bcr-Abl protein localizes to the cytoplasm in transformed cells but can enter the nucleus upon treatment with imatinib. Using leptomycin B, a nuclear export blocker, it has been shown that reactivated nuclear Bcr-Abl kinase activity can induce cell death, thus presenting an interesting potential treatment option for imatinib resistant disease. Here we show that the combination of imatinib and leptomycin B effectively induces cell death in imatinib-resistant Ba/F3 cells which display Bcr-Abl amplification or signs of clonal evolution. However, no such synergism is observed in imatinib-resistant Ba/F3 cells carrying the T315I mutation of Bcr-Abl or those which have lost Bcr-Abl expression. Thus, a partial inhibition of Bcr-Abl by imatinib is required for this approach in agreement with the proposed mode of action.
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| Authors | Rama Krishna Kancha, Nikolas von Bubnoff, Cornelius Miething, Christian Peschel, Katharina S Götze, Justus Duyster |
| Journal | Haematologica (Haematologica) Vol. 93 Issue 11 Pg. 1718-22 (Nov 2008) ISSN: 1592-8721 [Electronic] Italy |
| PMID | 18728023 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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