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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus / drug effects
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Adenocarcinoma / drug therapy
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Adenocarcinoma / metabolism*
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Adenocarcinoma / pathology
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Adenocarcinoma of Lung
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Animals
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use
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Cell Line, Tumor
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Drug Resistance, Neoplasm
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Drug Synergism
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Enzyme Activation
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ErbB Receptors / antagonists & inhibitors
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ErbB Receptors / metabolism*
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Erlotinib Hydrochloride
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Female
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Forkhead Box Protein O1
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / metabolism*
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Gene Expression Regulation, Neoplastic
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Humans
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Kruppel-Like Factor 6
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Kruppel-Like Transcription Factors / genetics
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Kruppel-Like Transcription Factors / metabolism*
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Lung Neoplasms / drug therapy
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Lung Neoplasms / metabolism*
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Lung Neoplasms / pathology
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Mutation
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-akt / metabolism
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Quinazolines / pharmacology
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Quinazolines / therapeutic use
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Real-Time Polymerase Chain Reaction
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Signal Transduction
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Transcription, Genetic
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Trifluoperazine / pharmacology
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Tumor Burden / drug effects
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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FOXO1 protein, human
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Forkhead Box Protein O1
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Forkhead Transcription Factors
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KLF6 protein, human
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Kruppel-Like Factor 6
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Kruppel-Like Transcription Factors
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Proto-Oncogene Proteins
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Quinazolines
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Trifluoperazine
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Erlotinib Hydrochloride
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ErbB Receptors
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Proto-Oncogene Proteins c-akt