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Ligandos autocrinos en la resistencia a erlotinib del cáncer pancreático

Pancreatic adenocarcinoma is one of the solid tumors with poorest prognosis. Its growing incidence projects it to be the second cause of cancer-related deaths after 2030. Self-sufficiency of growth factors and deregulation of ErbB receptors signaling pathways have been shown to play a fundamental role in its etiology. One of the mechanisms used by the tumor cell for the aberrant activation of this family of receptors is the autocrine secretion of EGF-related ligands. In the last years, therapies targeting ErbB receptors have emerged, but they have shown limited efficacy in pancreatic cancer. The overexpression of ErbB receptors and their ligands has demonstrated a critical participation in acquired resistance to these therapies. In the present study, we aimed to evaluate the contribution of this phenomenon to the tumorigenesis of pancreatic cancer and insensitivity to EGFR inhibitors. To this end, we used four pancreatic cancer cell lines (AsPc-1, BxPc3, Capan-1 and HPAF-II) and evaluated its sensitivity to EGFR inhibitor erlotinib, an FDA-approved drug for the treatment of pancreatic adenocarcinomas in combination with gemcitabine. We determined the expression of ErbB receptors shown by each cell line and chose two of them (BxPc-3 and HPAF-II) to analyze by RTPCR the gene expression of three EGF-related ligands (NRG-1, EPRR and TFG-α), prior and after treatment with erlotinib. EGFR inhibition rapidly produced an enhanced expression of EPR and TGF-α ligands in BxPc3, while HPAF-II downregulated both growth factors. Taken together, our findings demonstrate that treatment with erlotinib induces a change in gene expression of pancreatic cancer cell lines, which confers them a previously unrecognized mechanism of acquired resistance, allowing them to evade the cytostatic effects of this drug

Manager: Llorens Duran, Rafael de
Other contributions: Universitat de Girona. Facultat de Ciències
Author: Gámez García-Cervigón, Andrés
Date: 2018 September
Abstract: Pancreatic adenocarcinoma is one of the solid tumors with poorest prognosis. Its growing incidence projects it to be the second cause of cancer-related deaths after 2030. Self-sufficiency of growth factors and deregulation of ErbB receptors signaling pathways have been shown to play a fundamental role in its etiology. One of the mechanisms used by the tumor cell for the aberrant activation of this family of receptors is the autocrine secretion of EGF-related ligands. In the last years, therapies targeting ErbB receptors have emerged, but they have shown limited efficacy in pancreatic cancer. The overexpression of ErbB receptors and their ligands has demonstrated a critical participation in acquired resistance to these therapies. In the present study, we aimed to evaluate the contribution of this phenomenon to the tumorigenesis of pancreatic cancer and insensitivity to EGFR inhibitors. To this end, we used four pancreatic cancer cell lines (AsPc-1, BxPc3, Capan-1 and HPAF-II) and evaluated its sensitivity to EGFR inhibitor erlotinib, an FDA-approved drug for the treatment of pancreatic adenocarcinomas in combination with gemcitabine. We determined the expression of ErbB receptors shown by each cell line and chose two of them (BxPc-3 and HPAF-II) to analyze by RTPCR the gene expression of three EGF-related ligands (NRG-1, EPRR and TFG-α), prior and after treatment with erlotinib. EGFR inhibition rapidly produced an enhanced expression of EPR and TGF-α ligands in BxPc3, while HPAF-II downregulated both growth factors. Taken together, our findings demonstrate that treatment with erlotinib induces a change in gene expression of pancreatic cancer cell lines, which confers them a previously unrecognized mechanism of acquired resistance, allowing them to evade the cytostatic effects of this drug
Format: application/pdf
Document access: http://hdl.handle.net/10256/16411
Language: spa
Collection: Biotecnologia (TFG)
Rights: Attribution-NonCommercial-NoDerivatives 4.0 International
Rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
Subject: Factor de creixement epidèrmic -- Receptors
Adenocarcinoma
Pàncrees -- Càncer -- Investigació
Erlotinib
Medicaments antineoplàstics
Epidermal growth factor
Pancreas -- Cancer -- Research
Antineoplastic agents
Title: Ligandos autocrinos en la resistencia a erlotinib del cáncer pancreático
Type: info:eu-repo/semantics/bachelorThesis
Repository: DUGiDocs

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