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Mechanisms of Resistance in Gastroenteropancreatic Neuroendocrine Tumors

SIMPLE SUMMARY: Advanced neuroendocrine tumors originating in the intestinal tract and pancreas are treated with biologics that activate somatostatin receptors (lanreotide and octreotide), small molecule drugs that target the mTOR (everolimus) and VEGF and other signaling pathways (sunitinib), chemo...

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Autores principales: Shi, Chanjuan, Morse, Michael A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9776394/
https://www.ncbi.nlm.nih.gov/pubmed/36551599
http://dx.doi.org/10.3390/cancers14246114
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author Shi, Chanjuan
Morse, Michael A.
author_facet Shi, Chanjuan
Morse, Michael A.
author_sort Shi, Chanjuan
collection PubMed
description SIMPLE SUMMARY: Advanced neuroendocrine tumors originating in the intestinal tract and pancreas are treated with biologics that activate somatostatin receptors (lanreotide and octreotide), small molecule drugs that target the mTOR (everolimus) and VEGF and other signaling pathways (sunitinib), chemotherapies (temozolomide, capecitabine, fluorouracil, platinums), and receptor-targeted radionuclides (Lu177-DOTATATE). These treatments eventually fail to control tumor progression, but the mechanisms for therapeutic resistance are poorly understood. We will review preclinical and early clinical studies that provide insight into potential etiologies and new therapies and combinations that may address this resistance. ABSTRACT: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs), although curable when localized, frequently metastasize and require management with systemic therapies, including somatostatin analogues, peptide receptor radiotherapy, small-molecule targeted therapies, and chemotherapy. Although effective for disease control, these therapies eventually fail as a result of primary or secondary resistance. For small-molecule targeted therapies, the feedback activation of the targeted signaling pathways and activation of alternative pathways are prominent mechanisms, whereas the acquisition of additional genetic alterations only rarely occurs. For somatostatin receptor (SSTR)-targeted therapy, the heterogeneity of tumor SSTR expression and dedifferentiation with a downregulated expression of SSTR likely predominate. Hypoxia in the tumor microenvironment and stromal constituents contribute to resistance to all modalities. Current studies on mechanisms underlying therapeutic resistance and options for management in human GEP-NETs are scant; however, preclinical and early-phase human studies have suggested that combination therapy targeting multiple pathways or novel tyrosine kinase inhibitors with broader kinase inhibition may be promising.
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spelling pubmed-97763942022-12-23 Mechanisms of Resistance in Gastroenteropancreatic Neuroendocrine Tumors Shi, Chanjuan Morse, Michael A. Cancers (Basel) Review SIMPLE SUMMARY: Advanced neuroendocrine tumors originating in the intestinal tract and pancreas are treated with biologics that activate somatostatin receptors (lanreotide and octreotide), small molecule drugs that target the mTOR (everolimus) and VEGF and other signaling pathways (sunitinib), chemotherapies (temozolomide, capecitabine, fluorouracil, platinums), and receptor-targeted radionuclides (Lu177-DOTATATE). These treatments eventually fail to control tumor progression, but the mechanisms for therapeutic resistance are poorly understood. We will review preclinical and early clinical studies that provide insight into potential etiologies and new therapies and combinations that may address this resistance. ABSTRACT: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs), although curable when localized, frequently metastasize and require management with systemic therapies, including somatostatin analogues, peptide receptor radiotherapy, small-molecule targeted therapies, and chemotherapy. Although effective for disease control, these therapies eventually fail as a result of primary or secondary resistance. For small-molecule targeted therapies, the feedback activation of the targeted signaling pathways and activation of alternative pathways are prominent mechanisms, whereas the acquisition of additional genetic alterations only rarely occurs. For somatostatin receptor (SSTR)-targeted therapy, the heterogeneity of tumor SSTR expression and dedifferentiation with a downregulated expression of SSTR likely predominate. Hypoxia in the tumor microenvironment and stromal constituents contribute to resistance to all modalities. Current studies on mechanisms underlying therapeutic resistance and options for management in human GEP-NETs are scant; however, preclinical and early-phase human studies have suggested that combination therapy targeting multiple pathways or novel tyrosine kinase inhibitors with broader kinase inhibition may be promising. MDPI 2022-12-12 /pmc/articles/PMC9776394/ /pubmed/36551599 http://dx.doi.org/10.3390/cancers14246114 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Shi, Chanjuan
Morse, Michael A.
Mechanisms of Resistance in Gastroenteropancreatic Neuroendocrine Tumors
title Mechanisms of Resistance in Gastroenteropancreatic Neuroendocrine Tumors
title_full Mechanisms of Resistance in Gastroenteropancreatic Neuroendocrine Tumors
title_fullStr Mechanisms of Resistance in Gastroenteropancreatic Neuroendocrine Tumors
title_full_unstemmed Mechanisms of Resistance in Gastroenteropancreatic Neuroendocrine Tumors
title_short Mechanisms of Resistance in Gastroenteropancreatic Neuroendocrine Tumors
title_sort mechanisms of resistance in gastroenteropancreatic neuroendocrine tumors
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9776394/
https://www.ncbi.nlm.nih.gov/pubmed/36551599
http://dx.doi.org/10.3390/cancers14246114
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