[PMID]: | 28285180 |
[Au] Autor: | Suchowski K; Pöschinger T; Rehemtulla A; Stürzl M; Scheuer W |
[Ad] Endereço: | Discovery Oncology, Pharmaceutical Research and Early Development (pRED), Roche Innovation Center Munich, Penzberg, Germany. Electronic address: Karina.Suchowski@roche.com. |
[Ti] Título: | Noninvasive Bioluminescence Imaging of AKT Kinase Activity in Subcutaneous and Orthotopic NSCLC Xenografts: Correlation of AKT Activity with Tumor Growth Kinetics. |
[So] Source: | Neoplasia;19(4):310-320, 2017 Apr. |
[Is] ISSN: | 1476-5586 |
[Cp] País de publicação: | United States |
[La] Idioma: | eng |
[Ab] Resumo: | Aberrant signaling through the AKT kinase mediates oncogenic phenotypes including cell proliferation, survival, and therapeutic resistance. Here, we utilize a bioluminescence reporter for AKT kinase activity (BAR) to noninvasively assess the therapeutic efficacy of the EGFR inhibitor erlotinib in KRAS-mutated lung cancer therapy. A549 non-small cell lung cancer cell line, engineered to express BAR, enabled the evaluation of compounds targeting the EGFR/PI3K/AKT pathway in vitro as well as in mouse models. We found that erlotinib treatment of resistant A549 subcutaneous and orthotopic xenografts resulted in significant AKT inhibition as determined by an 8- to 13-fold (P < .0001) increase in reporter activity 3 hours after erlotinib (100 mg/kg) administration compared to the control. This was confirmed by a 25% (P < .0001) decrease in pAKT ex vivo and a decrease in tumor growth. Treatment of the orthotopic xenograft with varying doses of erlotinib (25, 50, and 100 mg/kg) revealed a dose- and time-dependent increase in reporter activity (10-, 12-, and 23-fold). Correspondingly, a decrease in phospho-AKT levels (0%, 16%, and 28%, respectively) and a decrease in the AKT dependent proliferation marker PCNA (0%, 50%, and 50%) were observed. We applied µ-CT imaging for noninvasive longitudinal quantification of lung tumor load which revealed a corresponding decrease in tumor growth in a dose-dependent manner. These findings demonstrate the utility of BAR to noninvasively monitor AKT activity in preclinical studies in response to AKT modulating agents. These results also demonstrate that BAR can be applied to study drug dosing, drug combinations, and treatment efficacy in orthotopic mouse lung tumor models. |
[Mh] Termos MeSH primário: |
Medições Luminescentes Imagem Molecular Neoplasias/metabolismo Neoplasias/patologia Proteínas Proto-Oncogênicas c-akt/metabolismo
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[Mh] Termos MeSH secundário: |
Animais Caspase 3/metabolismo Linhagem Celular Tumoral Modelos Animais de Doenças Ativação Enzimática Expressão Gênica Genes Reporter Xenoenxertos Seres Humanos Cinésica Medições Luminescentes/métodos Camundongos Modelos Biológicos Imagem Molecular/métodos Neoplasias/diagnóstico por imagem Fosfatidilinositol 3-Quinases/metabolismo Fosforilação Inibidores de Proteínas Quinases/farmacologia Proteínas Proto-Oncogênicas c-akt/genética Receptor do Fator de Crescimento Epidérmico/metabolismo Transdução de Sinais Carga Tumoral Microtomografia por Raio-X Ensaios Antitumorais Modelo de Xenoenxerto
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[Pt] Tipo de publicação: | JOURNAL ARTICLE |
[Nm] Nome de substância:
| 0 (Protein Kinase Inhibitors); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.10.1 (Receptor, Epidermal Growth Factor); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 3.4.22.- (Caspase 3) |
[Em] Mês de entrada: | 1708 |
[Cu] Atualização por classe: | 170807 |
[Lr] Data última revisão:
| 170807 |
[Sb] Subgrupo de revista: | IM |
[Da] Data de entrada para processamento: | 170313 |
[St] Status: | MEDLINE |
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