title: Overcoming the resistance to crizotinib in patients with non-small cell lung cancer harboring EML4/ALK translocation.
abstract: The large knowledge learned in molecular biology specifically in the oncology field during the last ten years has resulted in fruitful results for the treatment of non-small cell lung cancer. The first pathway to be effectively targeted in lung cancer was the epidermal growth factor receptor. The acceptance of epidermal growth factor receptor mutation as a strong predictive biomarker in non-small cell lung carcinoma has encouraged the search for more targets. In 2011, regulatory entities granted conditional approval to an anaplastic lymphoma kinase inhibitor (crizotinib) based on an impressive overall response rate in previously treated non-small cell lung cancer patients whose tumors harbored EML4/ALK translocations. The landmark approval of crizotinib based on early promising clinical data highlights the remarkable success of molecular medicine in lung cancer therapeutics. The cumulative data developed after that approval has confirmed the appropriateness of this decision as recently reported phase III has now demonstrated. Unfortunately, resistance to this agent invariably develops and we now face the challenge of understanding several resistance pathways and overcoming them with new and more potent compounds. New agents in clinical development such as alectinib, LDK378, AP26113, and AUY922 have not only demonstrated promising activity in crizotinib resistant patients, but also crossing new pharmacokinetic boundaries in ALK inhibition as potent CNS penetration.
authors.affiliation: Division of Medical Oncology and Hematology, James Graham Brown Cancer Center, University of Louisville, 529 S Jackson Street, Suite 426, Louisville, KY 40202, USA. Electronic address: capere06@louisville.edu.
authors.forename: Cesar A
authors.initials: CA
authors.lastname: Perez
authors.affiliation: Division of Hematology/Oncology, Sylvester Comprehensive Cancer Center, University of Miami, Leonard M. Miller School of Medicine, 1475 NW 12th Avenue, D8-4, Miami, FL 33136, USA. Electronic address: mvelez9@med.miami.edu.
authors.forename: Michel
authors.initials: M
authors.lastname: Velez
authors.affiliation: Memorial Cancer Institute, Memorial Health Care System, Boca Raton, FL, USA. Electronic address: lraez@mhs.net.
authors.forename: Luis E
authors.initials: LE
authors.lastname: Raez
authors.affiliation: Thoracic Oncology Program, Lynn Cancer Institute, Boca Raton, FL, USA. Electronic address: santose@fau.edu.
authors.forename: Edgardo S
authors.initials: ES
authors.lastname: Santos
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; D018797:Cell Cycle Proteins / Q000235:genetics; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000235:genetics; D058990:Molecular Targeted Therapy; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics; D014178:Translocation, Genetic
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C415585:EML4 protein, human; D012697:Serine Endopeptidases
keywords: AP26113; AUY922; Alectinib; Crizotinib; EML-4/ALK translocation; L1196 mutation; LDK378