title: Treating patients with ALK-rearranged non-small-cell lung cancer: mechanisms of resistance and strategies to overcome it.
abstract: Anaplastic lymphoma kinase (ALK) rearrangement is detected in 3-7% of patients with non-small-cell lung cancer. Crizotinib is an ALK inhibitor, which was approved in 2011 for the treatment of ALK-positive lung cancer. Despite the initial enthusiasm, most of the patients develop resistance within the first year of treatment. The main mechanisms are secondary mutations and bypass track activation. Moreover, crizotinib has low penetration into the central nervous system. The need to overcome these limitations has led to the development of second-generation inhibitors that have better effectiveness against crizotinib-resistant mutations and brain metastases. Ceritinib and alectinib are the only approved drugs of this group. Many ongoing trials try to define the most appropriate agent for the treatment of ALK-positive lung cancer depending on the responsible mechanism. This review focuses on the current data regarding the potential mechanisms of resistance to ALK inhibitors and the strategies to overcome it.
authors.affiliation: St. Savvas Regional Hospital for Cancer Treatment, 171 Alexandras Avenue, 11522, Athens, Greece.
authors.forename: M
authors.initials: M
authors.lastname: Drizou
authors.affiliation: Oncology Unit, Athens School of Medicine, Sotiria General Hospital, 152 Mesogion Avenue, 11527, Athens, Greece. ilkotteas@hotmail.com.
authors.forename: E A
authors.initials: EA
authors.lastname: Kotteas
authors.affiliation: Oncology Unit, Athens School of Medicine, Sotiria General Hospital, 152 Mesogion Avenue, 11527, Athens, Greece.
authors.forename: N
authors.initials: N
authors.lastname: Syrigos
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D015321:Gene Rearrangement; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
keywords: ALK rearrangement; ALK-positive NSCLC; Alectinib; Ceritinib; Crizotinib; Resistance mechanism