title: Resistance to Crizotinib in Advanced Non-Small Cell Lung Cancer (NSCLC) with ALK Rearrangement: Mechanisms, Treatment Strategies and New Targeted Therapies.
abstract: Non-small cell lung cancers (NSCLCs) harboring anaplastic lymphoma kinase (ALK) rearrangement are generally responsive to treatment with ALK tyrosine kinase inhibitors (TKIs). Crizotinib is the first-in-class TKI approved as front-line or salvage therapy in advanced ALK-rearranged NSCLC. Unfortunately, drug resistance develops after initial benefit, through a variety of mechanisms preserving or not the dominance of ALK signaling in the crizotinib-resistant state. The distinction between patients who preserve ALK dominance (secondary mutations alone or in combination with the number of copy ALK gain) compared to those that have decreased ALK dominance (separate or second oncogenic drivers, with or without concurrent persistence of the original ALK signal) is important in order to overcome resistance. Novel second-generation ALK inhibitors are currently in clinical development with promising results in ALK-rearranged NSCLC, as well as in crizotinib-resistant patients. Among these, ceritinib in the United States was granted by Food and Drug Administration accelerated approval for treatment of patients with ALK-rearranged, metastatic NSCLC with progression disease on or intolerance to crizotinib. Fully understanding of the different mechanisms of resistance to crizotinib will help us to continue to exploit personalized medicine approaches overcoming crizotinib resistance in these patients in the future. This review aims to discuss on strategy overcoming crizotinib-resistance starting from molecular mechanisms of resistance until novel ALK kinase inhibitors in ALK-rearranged NSCLC patients.
authors.forename: Francesca
authors.initials: F
authors.lastname: Casaluce
authors.forename: Assunta
authors.initials: A
authors.lastname: Sgambato
authors.forename: Paola Claudia
authors.initials: PC
authors.lastname: Sacco
authors.forename: Giovanni
authors.initials: G
authors.lastname: Palazzolo
authors.forename: Paolo
authors.initials: P
authors.lastname: Maione
authors.forename: Antonio
authors.initials: A
authors.lastname: Rossi
authors.forename: Fortunato
authors.initials: F
authors.lastname: Ciardiello
authors.affiliation: Division of Medical Oncology, "S. G. Moscati" Hospital, Avellino, Italy. cgridelli@libero.it.
authors.forename: Cesare
authors.initials: C
authors.lastname: Gridelli
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000077547:Crizotinib; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D015321:Gene Rearrangement; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D058990:Molecular Targeted Therapy; 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*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases