Anaplastic Lymphoma Kinase as a Cancer Target in Pediatric Malignancies.
In this era of more rational therapies, substantial efforts are being made to identify optimal targets. The discovery of translocations involving the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase in a subset of non-small cell lung cancers has become a paradigm for precision medicine. Notably, ALK was initially discovered as the fusion gene in anaplastic large cell non-Hodgkin lymphoma, a disease predominantly of childhood. The discovery of activating kinase domain mutations of the full-length ALK receptor as the major cause of hereditary neuroblastoma, and that somatically acquired mutations and amplification events often drive the malignant process in a subset of sporadic tumors, has established ALK as a tractable molecular target across histologically diverse tumors in which ALK is a critical mediator of oncogenesis. We are now uncovering the reexpression of this developmentally regulated protein in a broader subset of pediatric cancers, providing therapeutic targeting opportunities for diseases with shared molecular etiology. This review focuses on the role of ALK in pediatric malignancies, alongside the prospects and challenges associated with the development of effective ALK-inhibition strategies.
Division of Oncology and Center for Childhood Cancer Research, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. mosse@chop.edu.
Yael P
YP
Mossé
D000293:Adolescent; D000367:Age Factors; D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D006801:Humans; D007167:Immunotherapy; D007223:Infant; D007231:Infant, Newborn; D058990:Molecular Targeted Therapy; D009154:Mutation; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism*; D009447:Neuroblastoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D021381:Protein Transport; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases