Identification of WEE1 as a target to make AKT inhibition more effective in melanoma
| Autor: | Arati Sharma, Omer F. Kuzu, Raghavendra Gowda, Gregory R. Kardos, Mohammad A. Noory, SubbaRao V. Madhunapantula, Gavin P. Robertson, Joseph J. Drabick |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cancer Research Skin Neoplasms DNA Repair Cell Survival Mice Nude Apoptosis Cell Cycle Proteins Biology AKT3 Mice 03 medical and health sciences 0302 clinical medicine RNA interference Cell Line Tumor Antineoplastic Combined Chemotherapy Protocols medicine Animals Humans RNA Small Interfering Melanoma Protein Kinase Inhibitors Protein kinase B Transcription factor Cell Proliferation Pharmacology Sequence Analysis RNA Kinase Cell Cycle Nuclear Proteins Drug Synergism Protein-Tyrosine Kinases medicine.disease Xenograft Model Antitumor Assays Research Papers Wee1 Treatment Outcome 030104 developmental biology Oncology Gene Knockdown Techniques 030220 oncology & carcinogenesis biology.protein FOXM1 Cancer research Molecular Medicine Female Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Cancer Biology & Therapy. 19:53-62 |
| ISSN: | 1555-8576 1538-4047 |
| DOI: | 10.1080/15384047.2017.1360446 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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