EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors.
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.).
Choi
Young Lim
YL
Division of Functional Genomics, Jichi Medical University, Tochigi, Japan.
Soda
Manabu
M
Yamashita
Yoshihiro
Y
Ueno
Toshihide
T
Takashima
Junpei
J
Nakajima
Takahiro
T
Yatabe
Yasushi
Y
Takeuchi
Kengo
K
Hamada
Toru
T
Haruta
Hidenori
H
Ishikawa
Yuichi
Y
Kimura
Hideki
H
Mitsudomi
Tetsuya
T
Tanio
Yoshiro
Y
Mano
Hiroyuki
H
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*
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