The rise and fall of gatekeeper mutations? The BCR-ABL1 T315I paradigm.
review · Level V
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- Record sourced from PubMed, PMID 21732333.
- Also identified by DOI 10.1002/cncr.26225 and PMC identifier 6896214.
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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.
Medical subject headings
- Antineoplastic Agents
- Drug Resistance, Neoplasm
- Fusion Proteins, bcr-abl
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive
- Mutation
- Protein Kinase Inhibitors
- Protein-Tyrosine Kinases