Noninvasive Bioluminescence Imaging of AKT Kinase Activity in Subcutaneous and Orthotopic NSCLC Xenografts: Correlation of AKT Activity with Tumor Growth Kinetics

摘要: Abstract Aberrant signaling through the AKT kinase mediates oncogenic phenotypes including cell proliferation, survival, and therapeutic resistance. Here, we utilize a bioluminescence reporter for activity (BAR) to noninvasively assess efficacy of EGFR inhibitor erlotinib in KRAS-mutated lung cancer therapy. A549 non–small line, engineered express BAR, enabled evaluation compounds targeting EGFR/PI3K/AKT pathway vitro as well mouse models. We found that treatment resistant subcutaneous orthotopic xenografts resulted significant inhibition determined by an 8- 13-fold ( P ex vivo decrease tumor growth. Treatment xenograft with varying doses (25, 50, 100 mg/kg) revealed dose- time-dependent increase (10-, 12-, 23-fold). Correspondingly, phospho-AKT levels (0%, 16%, 28%, respectively) dependent proliferation marker PCNA 50%, 50%) were observed. applied μ-CT imaging noninvasive longitudinal quantification load which corresponding growth dose-dependent manner. These findings demonstrate utility BAR monitor preclinical studies response modulating agents. results also can be study drug dosing, combinations,