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.
Keywords:
cell-cycle checkpoint; cellular senescence; cyclin-dependent kinase; melanoma; targeted therapy.
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use*
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Cell Cycle Checkpoints / drug effects
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Cellular Senescence / drug effects
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Cellular Senescence / physiology
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Clinical Trials as Topic
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Cyclin-Dependent Kinases / antagonists & inhibitors*
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Cyclin-Dependent Kinases / physiology
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Drug Screening Assays, Antitumor
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Gene Expression Regulation, Neoplastic / drug effects
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Genes, ras
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Humans
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Melanoma / drug therapy*
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Melanoma / enzymology
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Melanoma / secondary
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Mice
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / physiology
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Molecular Targeted Therapy*
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Neoplasm Proteins / antagonists & inhibitors*
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use*
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Proto-Oncogene Proteins B-raf / antagonists & inhibitors
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Proto-Oncogene Proteins B-raf / genetics
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Proto-Oncogene Proteins B-raf / physiology
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Retinoblastoma Protein / antagonists & inhibitors
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Retinoblastoma Protein / genetics
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Retinoblastoma Protein / physiology
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Signal Transduction / drug effects
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ras Proteins / antagonists & inhibitors
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ras Proteins / physiology
Substances
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Antineoplastic Agents
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Neoplasm Proteins
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Protein Kinase Inhibitors
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Retinoblastoma Protein
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BRAF protein, human
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Proto-Oncogene Proteins B-raf
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Cyclin-Dependent Kinases
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Mitogen-Activated Protein Kinases
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ras Proteins