title: Molecular mechanisms that underpin EML4-ALK driven cancers and their response to targeted drugs.
abstract: A fusion between the EML4 (echinoderm microtubule-associated protein-like) and ALK (anaplastic lymphoma kinase) genes was identified in non-small cell lung cancer (NSCLC) in 2007 and there has been rapid progress in applying this knowledge to the benefit of patients. However, we have a poor understanding of EML4 and ALK biology and there are many challenges to devising the optimal strategy for treating EML4-ALK NSCLC patients. In this review, we describe the biology of EML4 and ALK, explain the main features of EML4-ALK fusion proteins and outline the therapies that target EML4-ALK. In particular, we highlight the recent advances in our understanding of the structures of EML proteins, describe the molecular mechanisms of resistance to ALK inhibitors and assess current thinking about combinations of ALK drugs with inhibitors that target other kinases or Hsp90.
authors.affiliation: Department of Molecular and Cell Biology, University of Leicester, Lancaster Road, Leicester, LE2 9HN, UK. r.w.bayliss@leeds.ac.uk.|Astbury Centre for Structural Molecular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK. r.w.bayliss@leeds.ac.uk.
authors.forename: Richard
authors.initials: R
authors.lastname: Bayliss
authors.affiliation: Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43 gil, Seoul, Korea.
authors.forename: Jene
authors.initials: J
authors.lastname: Choi
authors.affiliation: Cancer Research UK Centre, University of Leicester, Lancaster Road, Leicester, LE3 9SQ, UK.
authors.forename: Dean A
authors.initials: DA
authors.lastname: Fennell
authors.affiliation: Department of Molecular and Cell Biology, University of Leicester, Lancaster Road, Leicester, LE2 9HN, UK.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Fry
authors.affiliation: Department of Molecular and Cell Biology, University of Leicester, Lancaster Road, Leicester, LE2 9HN, UK.|Astbury Centre for Structural Molecular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Richards
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008869:Microtubule-Associated Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D015514:Oncogene Proteins, Fusion / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D012697:Serine Endopeptidases / Q000032:analysis / Q000235:genetics* / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; C522504:EML4-ALK fusion protein, human; D018841:HSP90 Heat-Shock Proteins; D008869:Microtubule-Associated Proteins; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C415585:EML4 protein, human; D012697:Serine Endopeptidases
keywords: Fusion; Kinase; Lung cancer; Oncogene; Structural biology