title: Targeting brain metastases in ALK-rearranged non-small-cell lung cancer.
abstract: The incidence of brain metastases has increased as a result of improved systemic control and advances in imaging. However, development of novel therapeutics with CNS activity has not advanced at the same rate. Research on molecular markers has revealed many potential targets for antineoplastic agents, and a particularly important aberration is translocation in the ALK gene, identified in non-small-cell lung cancer (NSCLC). ALK inhibitors have shown systemic efficacy against ALK-rearranged NSCLC in many clinical trials, but the effectiveness of crizotinib in CNS disease is limited by poor blood-brain barrier penetration and acquired drug resistance. In this Review, we discuss potential pathways to target ALK-rearranged brain metastases, including next generation ALK inhibitors with greater CNS penetration and mechanisms to overcome resistance. Other important mechanisms to control CNS disease include targeting pathways downstream of ALK phosphorylation, increasing the permeability of the blood-brain barrier, modifying the tumour microenvironment, and adding concurrent radiotherapy.
authors.affiliation: Department of Radiation Medicine, North Shore-Long Island Jewish Health System, Lake Success, NY, USA.
authors.forename: Isabella
authors.initials: I
authors.lastname: Zhang
authors.affiliation: Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Zaorsky
authors.affiliation: Department of Radiation Oncology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Palmer
authors.affiliation: Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: Ranee
authors.initials: R
authors.lastname: Mehra
authors.affiliation: Department of Radiation Oncology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, USA. Electronic address: Bo.Lu@jeffersonhospital.org.
authors.forename: Bo
authors.initials: B
authors.lastname: Lu
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000556:secondary; D002199:Capillary Permeability; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000556:secondary; D019008:Drug Resistance, Neoplasm; D015321:Gene Rearrangement; D020022:Genetic Predisposition to Disease; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D058990:Molecular Targeted Therapy; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000627:therapeutic use*; D018714:Radiotherapy, Adjuvant; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D059016:Tumor Microenvironment
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases