title: EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors.
abstract: The EML4 (echinoderm microtubule-associated protein-like 4)-ALK (anaplastic lymphoma kinase) fusion-type tyrosine kinase is an oncoprotein found in 4 to 5% of non-small-cell lung cancers, and clinical trials of specific inhibitors of ALK for the treatment of such tumors are currently under way. Here, we report the discovery of two secondary mutations within the kinase domain of EML4-ALK in tumor cells isolated from a patient during the relapse phase of treatment with an ALK inhibitor. Each mutation developed independently in subclones of the tumor and conferred marked resistance to two different ALK inhibitors. (Funded by the Ministry of Health, Labor, and Welfare of Japan, and others.).
authors.affiliation: Division of Functional Genomics, Jichi Medical University, Tochigi, Japan.
authors.forename: Young Lim
authors.initials: YL
authors.lastname: Choi
authors.forename: Manabu
authors.initials: M
authors.lastname: Soda
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yamashita
authors.forename: Toshihide
authors.initials: T
authors.lastname: Ueno
authors.forename: Junpei
authors.initials: J
authors.lastname: Takashima
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nakajima
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yatabe
authors.forename: Kengo
authors.initials: K
authors.lastname: Takeuchi
authors.forename: Toru
authors.initials: T
authors.lastname: Hamada
authors.forename: Hidenori
authors.initials: H
authors.lastname: Haruta
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Ishikawa
authors.forename: Hideki
authors.initials: H
authors.lastname: Kimura
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Mitsudomi
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Tanio
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mano
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000556:secondary; D000328:Adult; D000077548:Anaplastic Lymphoma Kinase; D018797:Cell Cycle Proteins / Q000235:genetics*; D000077547:Crizotinib; D018076:DNA, Complementary / Q000032:analysis; D004273:DNA, Neoplasm / Q000032:analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D015394:Molecular Structure; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics*; D011720:Pyrazoles / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D012334:RNA, Neoplasm / Q000032:analysis; D020794:Receptor Protein-Tyrosine Kinases; D017422:Sequence Analysis, DNA; D012697:Serine Endopeptidases / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; D018076:DNA, Complementary; D004273:DNA, Neoplasm; D008869:Microtubule-Associated Proteins; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D012334:RNA, Neoplasm; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; C415585:EML4 protein, human; D012697:Serine Endopeptidases