title: Cyclin-dependent kinases as therapeutic targets in melanoma.
abstract: Decades of scientific insights have led to a recent expansion of the therapeutic menu for melanoma. Despite these advances, the current targeted therapies and immune checkpoint agents continue to yield suboptimal response and cure rates. Hitherto, the most effective targeted therapy strategies have centered on effectors in the mitogen-activated protein kinase (MAPK) pathway. This review focuses on the emerging evidence of combinatorial approaches targeting both MAPK signaling and dysregulations in cell-cycle checkpoints. We discuss the prospects and limitations of utilizing strategies that promote cellular senescence, such as inhibition of the interphase cyclin-dependent kinases (CDKs) and highlight the current state of CDK drug discovery in melanoma.
authors.affiliation: Department of Dermatology, Columbia University Medical Center, New York, NY, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Miller
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects / Q000502:physiology; D002986:Clinical Trials as Topic; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D011905:Genes, ras; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000556:secondary; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D016160:Retinoblastoma Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D016160:Retinoblastoma Protein; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D018844:Cyclin-Dependent Kinases; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins
keywords: cell-cycle checkpoint; cellular senescence; cyclin-dependent kinase; melanoma; targeted therapy