| Abstract: |
EGFR activation is both a key molecular driver of disease progression and the target of a broad class of molecular agents designed to treat advanced cancer. Nevertheless, resistance develops through several mechanisms, including activation of AKT signaling. Though much is known about the specific molecular lesions conferring resistance to anti-EGFR-based therapies, additional molecular characterization of the downstream mediators of EGFR signaling may lead to the development of new classes of targeted molecular therapies to treat resistant disease. We identified a transcriptional network involving the tumor suppressors Krüppel-like factor 6 (KLF6) and forkhead box O1 (FOXO1) that negatively regulates activated EGFR signaling in both cell culture and in vivo models. Furthermore, the use of the FDA-approved drug trifluoperazine hydrochloride (TFP), which has been shown to inhibit FOXO1 nuclear export, restored sensitivity to AKT-driven erlotinib resistance through modulation of the KLF6/FOXO1 signaling cascade in both cell culture and xenograft models of lung adenocarcinoma. Combined, these findings define a novel transcriptional network regulating oncogenic EGFR signaling and identify a class of FDA-approved drugs as capable of restoring chemosensitivity to anti-EGFR-based therapy for the treatment of metastatic lung adenocarcinoma. |
| Keywords: |
signal transduction; protein kinase b; controlled study; protein expression; treatment response; mutation; proto-oncogene proteins; erlotinib; drug potentiation; nonhuman; antineoplastic agents; adenocarcinoma; forkhead transcription factors; mouse; animals; mice; animal tissue; lung neoplasms; epidermal growth factor receptor; animal experiment; animal model; in vivo study; receptor, epidermal growth factor; transcription, genetic; enzyme activation; tumor xenograft; drug resistance, neoplasm; xenograft model antitumor assays; cell line, tumor; phosphatidylinositol 3 kinase; mice, inbred balb c; cancer resistance; drug synergism; gene expression regulation, neoplastic; lung adenocarcinoma; mice, nude; messenger rna; tumor burden; phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase; proto-oncogene proteins c-akt; kruppel like factor 6; kruppel-like transcription factors; mitogen activated protein kinase 1; mitogen activated protein kinase 3; active transport, cell nucleus; down regulation; k ras protein; quinazolines; transcription factor fkhr; real-time polymerase chain reaction; trifluoperazine
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