title: The rise and fall of gatekeeper mutations? The BCR-ABL1 T315I paradigm.
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.
authors: Department of Thoracic, Head/Neck Medical Oncology and Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors: Don L
authors: DL
authors: Gibbons
authors: Sabrina
authors: S
authors: Pricl
authors: Hagop
authors: H
authors: Kantarjian
authors: Jorge
authors: J
authors: Cortes
authors: Alfonso
authors: A
authors: Quintás-Cardama
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D007093:Imidazoles / Q000494:pharmacology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics; D009154:Mutation; D010879:Piperazines; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics*; D011724:Pyridazines / Q000494:pharmacology; D011743:Pyrimidines
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D007093:Imidazoles; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D011743:Pyrimidines; C545373:ponatinib; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl