Abstract
While the clinical benefit of MEK inhibitor (MEKi)-based therapy is well established in Raf mutant malignancies, its utility as a suppressor of hyperactive MAPK signaling in the absence of mutated Raf or Ras, is an area of ongoing research. MAPK activation is associated with loss of ERα expression and hormonal resistance in numerous malignancies. Herein, we demonstrate that MEKi induces a feedback response that results in ERα overexpression, phosphorylation and transcriptional activation of ER-regulated genes. Mechanistically, MEKi-mediated ERα overexpression is largely independent of erbB2 and AKT feedback activation, but is ERK-dependent. We subsequently exploit this phenomenon therapeutically by combining the ER-antagonist, fulvestrant with MEKi. This results in synergistic suppression of tumor growth, in vitro and potentiation of single agent activity in vivo in nude mice bearing xenografts. Thus, we demonstrate that exploiting adaptive feedback after MEKi can be used to sensitize ERα-positive tumors to hormonal therapy, and propose that this strategy may have broader clinical utility in ERα-positive ovarian carcinoma.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents, Hormonal / pharmacology*
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Benzamides / pharmacology
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Carcinoma / drug therapy*
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Carcinoma / genetics
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Carcinoma / metabolism
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Carcinoma / pathology
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Cell Line, Tumor
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Diphenylamine / analogs & derivatives
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Diphenylamine / pharmacology
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Estradiol / analogs & derivatives
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Estradiol / pharmacology
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Estrogen Receptor alpha / agonists
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Estrogen Receptor alpha / genetics*
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Estrogen Receptor alpha / metabolism
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Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
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Extracellular Signal-Regulated MAP Kinases / genetics
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Feedback, Physiological / drug effects
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Female
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Fulvestrant
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Gene Expression Regulation, Neoplastic / drug effects*
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Heterocyclic Compounds, 3-Ring / pharmacology
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Humans
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Lapatinib
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MAP Kinase Kinase Kinases / antagonists & inhibitors
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MAP Kinase Kinase Kinases / genetics
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MAP Kinase Kinase Kinases / metabolism
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Mice
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Mice, Nude
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Ovarian Neoplasms / drug therapy*
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Ovarian Neoplasms / genetics
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Ovarian Neoplasms / metabolism
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Ovarian Neoplasms / pathology
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Phosphorylation / drug effects
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Protein Kinase Inhibitors / pharmacology*
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Quinazolines / pharmacology
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Signal Transduction / drug effects
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents, Hormonal
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Benzamides
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ESR1 protein, human
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Estrogen Receptor alpha
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Heterocyclic Compounds, 3-Ring
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MK 2206
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Protein Kinase Inhibitors
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Quinazolines
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Lapatinib
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Fulvestrant
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Estradiol
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mirdametinib
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Diphenylamine
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases
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MAP Kinase Kinase Kinases