SGX393 inhibits the CML mutant Bcr-AblT315I and preempts in vitro resistance when combined with nilotinib or dasatinib

Thomas O'Hare, Christopher A. Eide, Jeffrey W. Tyner, Amie S. Corbin, Matthew J. Wong, Sean Buchanan, Kevin Holme, Katayoun A. Jessen, Crystal Tang, Hal A. Lewis, Richard D. Romero, Stephen K. Burley, Michael W. Deininger

Research output: Contribution to journalArticle

63 Scopus citations

Abstract

Imatinib inhibits Bcr-Abl, the oncogenic tyrosine kinase that causes chronic myeloid leukemia. The second-line inhibitors nilotinib and dasatinib are effective in patients with imatinib resistance resulting from Bcr-Abl kinase domain mutations. Bcr-AblT315I, however, is resistant to all Abl kinase inhibitors in clinical use and is emerging as the most frequent cause of salvage therapy failure. SGX393 is a potent inhibitor of native and T315I-mutant Bcr-Abl kinase that blocks the growth of leukemia cell lines and primary hematopoietic cells expressing Bcr-AblT315I, with minimal toxicity against Bcr-Abl-negative cell lines or normal bone marrow. A screen for Bcr-Abl mutants emerging in the presence of SGX393 revealed concentration-dependent reduction in the number and range of mutations. Combining SGX393 with nilotinib or dasatinib preempted emergence of resistant subclones, including Bcr-Abl T315I. These findings suggest that combination of a T315I inhibitor with the current clinically used inhibitors may be useful for reduction of Bcr-Abl mutants in Philadelphia chromosome-positive leukemia.

Original languageEnglish (US)
Pages (from-to)5507-5512
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number14
DOIs
StatePublished - Apr 8 2008

Keywords

  • Gatekeeper mutation
  • Imatinib resistance
  • Kinase inhibitor

ASJC Scopus subject areas

  • General

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    O'Hare, T., Eide, C. A., Tyner, J. W., Corbin, A. S., Wong, M. J., Buchanan, S., Holme, K., Jessen, K. A., Tang, C., Lewis, H. A., Romero, R. D., Burley, S. K., & Deininger, M. W. (2008). SGX393 inhibits the CML mutant Bcr-AblT315I and preempts in vitro resistance when combined with nilotinib or dasatinib. Proceedings of the National Academy of Sciences of the United States of America, 105(14), 5507-5512. https://doi.org/10.1073/pnas.0800587105