The rise and fall of gatekeeper mutations? The BCR-ABL1 T315I paradigm

Authors

  • Don L. Gibbons MD, PhD,

    1. Department of Thoracic, Head/Neck Medical Oncology and Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
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    • The first 2 authors contributed equally to this article.

  • Sabrina Pricl PhD,

    1. Molecular Simulation Engineering Laboratory, Department of Materials and Natural Resources, University of Trieste, Trieste, Italy
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    • The first 2 authors contributed equally to this article.

  • Hagop Kantarjian MD,

    1. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas
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  • Jorge Cortes MD,

    1. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas
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  • Alfonso Quintás-Cardama MD

    Corresponding author
    1. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas
    • Department of Leukemia, Unit 428, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030

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    • Fax: (713) 745-4009


Abstract

The use of tyrosine kinase inhibitors (TKIs) has become an integral component of cancer therapy. Imatinib mesylate, a breakpoint cluster region-Abelson BCR-ABL1 inhibitor, was the first TKI approved in cancer medicine and has served as a model for the development of similar agents for other cancers. An important drawback of TKI therapy is the development of resistance, frequently through the acquisition of mutations. Mutations at the gatekeeper residues of BCR-ABL1 (eg, the threonine-to-isoleucine mutation at codon 315) and other oncogenic kinases have proven highly resistant to currently available TKIs. Advances in the structural biology of oncogenic kinases have facilitated the rational development of TKIs that are active against gatekeeper mutations. Cancer 2011;. © 2011 American Cancer Society.

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