title: Anaplastic lymphoma kinase rearrangement in lung cancer: its biological and clinical significance.
abstract: Anaplastic lymphoma kinase (ALK) has been found to fuse with other partners, such as echinoderm microtubule-associated protein-like 4 (EML4), leading to potent malignant transformation in lung cancer, specifically non-small-cell lung cancer (NSCLC). The frequency of the ALK rearrangement in patients with NSCLC is reported to be 4-7%, and the rearrangement is frequently observed in relatively younger patients, non- or light smokers and those with adenocarcinoma histology without other genetic disorders, such as mutations of the epidermal growth factor receptor gene. Crizotinib, which is a first-in-class ALK tyrosine kinase inhibitor (TKI), was shown to be effective and well tolerated in ALK-positive NSCLC patients by a single-arm phase I study. Furthermore, a phase III randomized study demonstrated the superiority of crizotinib to standard chemotherapy (pemetrexed or docetaxel) in the treatment of NSCLC patients harboring the ALK rearrangement who had received one prior platinum-based chemotherapy. However, the mechanisms of resistance to crizotinib are major concerns when administering crizotinib to ALK-positive NSCLC patients, and they include second mutations and a gain in the copy number of the ALK gene, activation of other oncogenes, etc. Treatment strategies to overcome these mechanisms of resistance have been developed, including the use of second-generation ALK inhibitors, such as alectinib and ceritinib, heat shock protein 90 inhibitors and so on. In this article, we review the pre-clinical and clinical data regarding the biologal and clinical significance of the ALK rearrangement in lung cancer.
authors.affiliation: Department of Thoracic Oncology, National Kyushu Cancer Center, 3-1-1 Notame, Minami-ku, Fukuoka 811-1395, Japan.
authors.forename: Gouji
authors.initials: G
authors.lastname: Toyokawa
authors.affiliation: Department of Thoracic Oncology, National Kyushu Cancer Center, 3-1-1 Notame, Minami-ku, Fukuoka 811-1395, Japan. Electronic address: tseto@nk-cc.go.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Seto
mesh_terms: D000367:Age Factors; D000077548:Anaplastic Lymphoma Kinase; D002227:Carbazoles; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology*; D000077547:Crizotinib; D066246:ErbB Receptors / Q000235:genetics; D050939:Gene Fusion; D015321:Gene Rearrangement; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000502:physiology; D058990:Molecular Targeted Therapy; D009154:Mutation; D015514:Oncogene Proteins, Fusion; D010880:Piperidines; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology; D012697:Serine Endopeptidases / Q000235:genetics / Q000502:physiology; D012907:Smoking / Q000235:genetics; D013450:Sulfones
chemical_list: D002227:Carbazoles; D018797:Cell Cycle Proteins; C522504:EML4-ALK fusion protein, human; D008869:Microtubule-Associated Proteins; D015514:Oncogene Proteins, Fusion; D010880:Piperidines; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D013450:Sulfones; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; C415585:EML4 protein, human; D012697:Serine Endopeptidases; C586847:ceritinib; C582670:alectinib
keywords: ALK inhibitors; Anaplastic lymphoma kinase; Non-small cell lung cancer; Oncogenic drivers