title: Structural modeling of V299L and E459K Bcr-Abl mutation, and sequential therapy of tyrosine kinase inhibitors for the compound mutations.
abstract: Sequential treatment with different tyrosine kinase inhibitors (TKIs) is one of the strategies for handling chronic myeloid leukemia (CML) in which dynamic change in Bcr-Abl kinase domain mutation is often an obstacle faced during TKI therapy. Here we report successful sequential therapy with different TKIs for the CML patient harboring V299L and E459K compound mutations. Molecular monitoring including quantitative analysis of BCR-ABL transcript level and mutation analysis were performed regularly for successful treatment. Additionally a drug-target complex was structurally modeled to investigate influence of amino acid substitutions on drug resistance, and to choose alternative TKI in sequential therapy, suggesting protein structural modeling can be useful approach in selecting alternative TKIs.
authors.affiliation: Molecular Hematology Research Laboratory, The Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Dongho
authors.initials: D
authors.lastname: Kim
authors.forename: Dong-Wook
authors.initials: DW
authors.lastname: Kim
authors.forename: Byung-Sik
authors.initials: BS
authors.lastname: Cho
authors.forename: Hyun-Gyung
authors.initials: HG
authors.lastname: Goh
authors.forename: Soo-Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Wan-Seok
authors.initials: WS
authors.lastname: Kim
authors.forename: Jeong
authors.initials: J
authors.lastname: Lee
authors.forename: Il-Young
authors.initials: IY
authors.lastname: Kweon
authors.forename: Sa-Hee
authors.initials: SH
authors.lastname: Park
authors.forename: Jeong Hyeok
authors.initials: JH
authors.lastname: Yoon
authors.forename: Nam Doo
authors.initials: ND
authors.lastname: Kim
authors.forename: Haarin
authors.initials: H
authors.lastname: Chun
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001549:Benzamides; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D009154:Mutation; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D016133:Polymerase Chain Reaction; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D012333:RNA, Messenger; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib