title: Overcoming crizotinib resistance in ALK-rearranged NSCLC with the second-generation ALK-inhibitor ceritinib.
abstract: In up to 5% of non-small cell lung cancer (NSCLC) patients, the EML4-ALK translocation drives tumor progression. Treatment with the ALK inhibitor crizotinib is more effective than standard chemotherapy. However, resistance to crizotinib occurs after approximately 8 months. Ceritinib is the first second-generation ALK inhibitor approved for treatment of crizotinib-resistant NSCLC. Ceritinib inhibits two of the most common ALK-mutants that confer resistance to crizotinib: L1196 M and G1269A. Cells with ALK expression are more sensitive to ceritinib than crizotinib (IC50 25 nM vs. 150 nM, respectively). Alternative second-generation ALK inhibitors such as Alectinib, Brigatinib and PF-06463922 are currently in development, each affecting different crizotinib-resistant ALK target mutations. Genetic identification of crizotinib-resistant mutants is essential for selecting the optimal treatment strategy in NSCLC patients to overcome resistance and to increase progression-free survival.
authors.affiliation: a Department of Medical Oncology , VU University Medical Center , Amsterdam , The Netherlands.
authors.forename: Ittai B
authors.initials: IB
authors.lastname: Muller
authors.affiliation: b Department of Medical Pulmonology , VU University Medical Center , Amsterdam , The Netherlands.
authors.forename: Adrianus J
authors.initials: AJ
authors.lastname: De Langen
authors.affiliation: a Department of Medical Oncology , VU University Medical Center , Amsterdam , The Netherlands.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Honeywell
authors.affiliation: a Department of Medical Oncology , VU University Medical Center , Amsterdam , The Netherlands.|c Cancer Pharmacology Lab , AIRC Start-Up Unit, DIPINT , Pisa , Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Giovannetti
authors.affiliation: a Department of Medical Oncology , VU University Medical Center , Amsterdam , The Netherlands.
authors.forename: Godefridus J
authors.initials: GJ
authors.lastname: Peters
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000077547:Crizotinib; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D013450:Sulfones / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D013450:Sulfones; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C586847:ceritinib
keywords: Acquired resistance; anaplastic lymphoma kinase; ceritinib; crizotinib; resistance mutation. EML-ALK; tyrosine kinase inhibitors