title: Clinical resistance to the kinase inhibitor STI-571 in chronic myeloid leukemia by mutation of Tyr-253 in the Abl kinase domain P-loop.
abstract: The Abl tyrosine kinase inhibitor STI-571 is effective therapy for stable phase chronic myeloid leukemia (CML) patients, but the majority of CML blast-crisis patients that respond to STI-571 relapse because of reactivation of Bcr-Abl signaling. Mutations of Thr-315 in the Abl kinase domain to Ile (T315I) were previously described in STI-571-resistant patients and likely cause resistance from steric interference with drug binding. Here we identify mutations of Tyr-253 in the nucleotide-binding (P) loop of the Abl kinase domain to Phe or His in patients with advanced CML and acquired STI-571 resistance. Bcr-Abl Y253F demonstrated intermediate resistance to STI-571 in vitro and in vivo when compared with Bcr-Abl T315I. The response of Abl proteins to STI-571 was influenced by the regulatory state of the kinase and by tyrosine phosphorylation. The sensitivity of purified c-Abl to STI-571 was increased by a dysregulating mutation (P112L) in the Src homology 3 domain of Abl but decreased by phosphorylation at the regulatory Tyr-393. In contrast, the Y253F mutation dysregulated c-Abl and conferred intrinsic but not absolute resistance to STI-571 that was independent of Tyr-393 phosphorylation. The Abl P-loop is a second target for mutations that confer resistance to STI-571 in advanced CML, and the Y253F mutation may impair the induced-fit interaction of STI-571 with the Abl catalytic domain rather than sterically blocking binding of the drug. Because clinical resistance induced by the Y253F mutation might be overcome by dose escalation of STI-571, molecular genotyping of STI-571-resistant patients may provide information useful for rational therapeutic management.
authors.affiliation: Center for Blood Research and Department of Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115-5717, USA.
authors.forename: Sergei
authors.initials: S
authors.lastname: Roumiantsev
authors.forename: Neil P
authors.initials: NP
authors.lastname: Shah
authors.forename: Mercedes E
authors.initials: ME
authors.lastname: Gorre
authors.forename: John
authors.initials: J
authors.lastname: Nicoll
authors.forename: Bradley B
authors.initials: BB
authors.lastname: Brasher
authors.forename: Charles L
authors.initials: CL
authors.lastname: Sawyers
authors.forename: Richard A
authors.initials: RA
authors.lastname: Van Etten
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D004351:Drug Resistance; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D010649:Phenylalanine / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D010879:Piperazines / Q000627:therapeutic use*; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D011743:Pyrimidines / Q000627:therapeutic use*; D014443:Tyrosine / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D014443:Tyrosine; D010649:Phenylalanine; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl