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Signaling Pathways mTOR and ERK as Therapeutic Targets in Sinonasal Intestinal-Type Adenocarcinoma
Helena Codina-Martínez1, Sara Lucila Lorenzo-Guerra1, Virginia N Cabal1
1Department of Head and Neck Cancer, Instituto de Investigación Sanitaria del Principado de Asturias, 33011 Oviedo, Spain.
Abstract:
Despite advances in surgery and radiotherapy, the overall prognosis of sinonasal intestinal-type adenocarcinoma (ITAC) is poor, and new treatment options are needed. Recent studies have indicated alterations in cellular signaling pathways that may serve as targets for modern inhibitors. Our aim was to evaluate the frequency of mTOR and ERK pathway upregulation in a retrospective series of 139 ITAC and to test the efficacy and mechanism of action of candidate targeted inhibitors in cell line ITAC-3. An immunohistochemical analysis on p-AKT, p-mTOR, p-S6, p-4E-BP1, and p-ERK indicated, respectively, a 68% and 57% mTOR and ERK pathway activation. In vitro studies using low doses of mTOR inhibitor everolimus and ERK inhibitor selumetinib showed significant growth inhibition as monotherapy and especially as combined therapy. This effect was accompanied by the downregulation of mTOR and ERK protein expression. Our data open a new and promising possibility for personalized treatment of ITAC patients.
Insights
Targeted therapies show promise for sinonasal intestinal-type adenocarcinoma (ITAC). mTOR and ERK pathway inhibitors, everolimus and selumetinib, significantly inhibited ITAC cell growth, offering new personalized treatment options.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Signaling
Background:
- Sinonasal intestinal-type adenocarcinoma (ITAC) has a poor prognosis despite current treatments.
- Alterations in cellular signaling pathways present potential therapeutic targets.
Purpose of the Study:
- To investigate the frequency of mTOR and ERK pathway activation in ITAC.
- To assess the efficacy of mTOR and ERK inhibitors in ITAC cell lines.
Main Methods:
- Immunohistochemical analysis of signaling pathway proteins in 139 ITAC samples.
- In vitro studies using ITAC-3 cell line treated with everolimus (mTOR inhibitor) and selumetinib (ERK inhibitor).
Main Results:
- 68% mTOR and 57% ERK pathway activation detected via immunohistochemistry.
- Everolimus and selumetinib demonstrated significant ITAC cell growth inhibition, particularly in combination therapy.
- Inhibitor treatment led to downregulation of mTOR and ERK protein expression.
Conclusions:
- mTOR and ERK pathways are frequently upregulated in ITAC.
- Targeted inhibition of mTOR and ERK pathways shows therapeutic potential for ITAC.
- Combined therapy with everolimus and selumetinib offers a promising strategy for personalized ITAC treatment.
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