Abstract
AKT3 is one of the major therapeutic targets in melanoma but clinically targeting AKT3 alone seems to be an ineffective therapeutic approach. To identify unique strategies to enhance the efficacy of targeting AKT3, a screen was undertaken where AKT3 was co-targeted with a panel of kinases important in melanoma development. The screen identified WEE1 as the most potent target that when inhibited along with AKT3 would enhance the efficacy of targeting AKT3 in melanoma. RNAi mediated inhibition of AKT3 and WEE1 synergistically inhibited the viability of melanoma cells leading to a 65-75% decrease in tumor development. This approach was effective by mechanistically modulating pathways associated with the transcription factors p53 and FOXM1. Simultaneously regulating the activity of these two transcriptionally driven pathways, cooperatively deregulated cell cycle control and DNA damage repair to synergistically kill melanoma cells. This study uniquely identifies a potential approach to improve the efficacy of targeting AKT3 in melanoma.
Keywords:
AKT3; Melanoma; WEE1; synergy.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Apoptosis / drug effects
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Apoptosis / genetics
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Cell Cycle / drug effects
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Cell Cycle / genetics
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Cell Cycle Proteins / antagonists & inhibitors*
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Proliferation / genetics
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Cell Survival / drug effects
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Cell Survival / genetics
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DNA Repair / drug effects
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DNA Repair / genetics
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Drug Synergism
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Female
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Gene Knockdown Techniques
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Humans
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Melanoma / drug therapy*
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Melanoma / genetics
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Melanoma / pathology
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Mice
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Mice, Nude
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Nuclear Proteins / antagonists & inhibitors*
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use
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Protein-Tyrosine Kinases / antagonists & inhibitors*
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Protein-Tyrosine Kinases / genetics
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Protein-Tyrosine Kinases / metabolism
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
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Proto-Oncogene Proteins c-akt / metabolism
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RNA, Small Interfering / metabolism
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Sequence Analysis, RNA
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Skin Neoplasms / drug therapy*
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Skin Neoplasms / genetics
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Skin Neoplasms / pathology
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Treatment Outcome
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Xenograft Model Antitumor Assays
Substances
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Cell Cycle Proteins
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Nuclear Proteins
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Protein Kinase Inhibitors
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RNA, Small Interfering
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Protein-Tyrosine Kinases
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WEE1 protein, human
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AKT3 protein, human
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Proto-Oncogene Proteins c-akt