title: Management of Resistance to Crizotinib in Anaplastic Lymphoma Kinase-Positive Non-Small-cell Lung Cancer.
abstract: During the past decade, the recognition of an ever-expanding list of driver oncogenic mutations in non-small-cell lung cancer has resulted in rapid therapeutic advances. Since the first description of the echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase (EML4-ALK) rearrangement in 4% of cases of non-small-cell lung cancer in 2007, a highly potent and selective ALK inhibitor, crizotinib, was developed and approved in record time. However, it soon became apparent that although the responses can be dramatic and durable and primary intrinsic resistance to crizotinib is uncommon, the emergence of secondary resistance is inevitable. Efforts to elucidate the specific mechanisms that confer acquired resistance to crizotinib are underway. These have led to the recognition of the role of secondary resistance mutations, of ALK amplification, and of activation of bypass signaling, all of which contribute to resistance to crizotinib. Moreover, the rapid preclinical and clinical development of multiple second-generation ALK inhibitors that exhibit significant clinical activity against crizotinib-resistant disease has provided multiple options to treating physicians, with the ultimate goal the delivery of tailored medicine.
authors.affiliation: Hellenic Oncology Research Group, Athens, Greece.
authors.forename: Alexios
authors.initials: A
authors.lastname: Matikas
authors.affiliation: Hellenic Oncology Research Group, Athens, Greece.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Kentepozidis
authors.affiliation: Hellenic Oncology Research Group, Athens, Greece.
authors.forename: Vassilis
authors.initials: V
authors.lastname: Georgoulias
authors.affiliation: Hellenic Oncology Research Group, Athens, Greece. Electronic address: info@horg.gr.
authors.forename: Athanasios
authors.initials: A
authors.lastname: Kotsakis
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D000077547:Crizotinib; D019468:Disease Management; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011720:Pyrazoles / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
keywords: ALK inhibitor; Alectinib; Ceritinib; EML4-ALK; NSCLC