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

Don L. Gibbons, Sabrina Pricl, Hagop Kantarjian, Jorge Cortes, Alfonso Quintás-Cardama

Research output: Contribution to journalComment/debate

50 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)293-299
Number of pages7
JournalCancer
Volume118
Issue number2
DOIs
StatePublished - Jan 15 2012
Externally publishedYes

Keywords

  • Chronic myeloid leukemia
  • Gatekeeper mutation
  • Ponatinib
  • Threonine-to-isoleucine mutation at codon 315
  • Tyrosine kinase inhibitor

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Gibbons, D. L., Pricl, S., Kantarjian, H., Cortes, J., & Quintás-Cardama, A. (2012). The rise and fall of gatekeeper mutations? The BCR-ABL1 T315I paradigm. Cancer, 118(2), 293-299. https://doi.org/10.1002/cncr.26225