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Sensitivity to Entrectinib Associated With a Novel LMNA-NTRK1 Gene Fusion in Metastatic Colorectal Cancer

In metastatic colorectal cancer (CRC), actionable genetic lesions represent potential clinical opportunities. NTRK1, 2, and 3 gene rearrangements encode oncogenic fusions of the tropomyosin-receptor kinase (TRK) family of receptor tyrosine kinases in different tumor types. The TPM3-NTRK1 rearrangeme...

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Autores principales: Sartore-Bianchi, Andrea, Ardini, Elena, Bosotti, Roberta, Amatu, Alessio, Valtorta, Emanuele, Somaschini, Alessio, Raddrizzani, Laura, Palmeri, Laura, Banfi, Patrizia, Bonazzina, Erica, Misale, Sandra, Marrapese, Giovanna, Leone, Antonella, Alzani, Rachele, Luo, David, Hornby, Zachary, Lim, Jonathan, Veronese, Silvio, Vanzulli, Angelo, Bardelli, Alberto, Martignoni, Marcella, Davite, Cristina, Galvani, Arturo, Isacchi, Antonella, Siena, Salvatore
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712682/
https://www.ncbi.nlm.nih.gov/pubmed/26563355
http://dx.doi.org/10.1093/jnci/djv306
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author Sartore-Bianchi, Andrea
Ardini, Elena
Bosotti, Roberta
Amatu, Alessio
Valtorta, Emanuele
Somaschini, Alessio
Raddrizzani, Laura
Palmeri, Laura
Banfi, Patrizia
Bonazzina, Erica
Misale, Sandra
Marrapese, Giovanna
Leone, Antonella
Alzani, Rachele
Luo, David
Hornby, Zachary
Lim, Jonathan
Veronese, Silvio
Vanzulli, Angelo
Bardelli, Alberto
Martignoni, Marcella
Davite, Cristina
Galvani, Arturo
Isacchi, Antonella
Siena, Salvatore
author_facet Sartore-Bianchi, Andrea
Ardini, Elena
Bosotti, Roberta
Amatu, Alessio
Valtorta, Emanuele
Somaschini, Alessio
Raddrizzani, Laura
Palmeri, Laura
Banfi, Patrizia
Bonazzina, Erica
Misale, Sandra
Marrapese, Giovanna
Leone, Antonella
Alzani, Rachele
Luo, David
Hornby, Zachary
Lim, Jonathan
Veronese, Silvio
Vanzulli, Angelo
Bardelli, Alberto
Martignoni, Marcella
Davite, Cristina
Galvani, Arturo
Isacchi, Antonella
Siena, Salvatore
author_sort Sartore-Bianchi, Andrea
collection PubMed
description In metastatic colorectal cancer (CRC), actionable genetic lesions represent potential clinical opportunities. NTRK1, 2, and 3 gene rearrangements encode oncogenic fusions of the tropomyosin-receptor kinase (TRK) family of receptor tyrosine kinases in different tumor types. The TPM3-NTRK1 rearrangement is a recurring event in CRC that renders tumors sensitive to TRKA kinase inhibitors in preclinical models. We identified abnormal expression of the TRKA protein in tumor and liver metastases of a CRC patient refractory to standard therapy. Molecular characterization unveiled a novel LMNA-NTRK1 rearrangement within chromosome 1 with oncogenic potential, and the patient was treated with the pan-TRK inhibitor entrectinib, achieving partial response with decrease in hepatic target lesions from 6.8 and 8.2cm in longest diameter to 4.7 and 4.3cm, respectively. To our knowledge, this is the first clinical evidence of efficacy for therapeutic inhibition of TRKA in a solid tumor, illuminating a genomic-driven strategy to identify CRCs reliant on this oncogene to be clinically targeted with entrectinib.
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spelling pubmed-47126822016-01-19 Sensitivity to Entrectinib Associated With a Novel LMNA-NTRK1 Gene Fusion in Metastatic Colorectal Cancer Sartore-Bianchi, Andrea Ardini, Elena Bosotti, Roberta Amatu, Alessio Valtorta, Emanuele Somaschini, Alessio Raddrizzani, Laura Palmeri, Laura Banfi, Patrizia Bonazzina, Erica Misale, Sandra Marrapese, Giovanna Leone, Antonella Alzani, Rachele Luo, David Hornby, Zachary Lim, Jonathan Veronese, Silvio Vanzulli, Angelo Bardelli, Alberto Martignoni, Marcella Davite, Cristina Galvani, Arturo Isacchi, Antonella Siena, Salvatore J Natl Cancer Inst Brief Communication In metastatic colorectal cancer (CRC), actionable genetic lesions represent potential clinical opportunities. NTRK1, 2, and 3 gene rearrangements encode oncogenic fusions of the tropomyosin-receptor kinase (TRK) family of receptor tyrosine kinases in different tumor types. The TPM3-NTRK1 rearrangement is a recurring event in CRC that renders tumors sensitive to TRKA kinase inhibitors in preclinical models. We identified abnormal expression of the TRKA protein in tumor and liver metastases of a CRC patient refractory to standard therapy. Molecular characterization unveiled a novel LMNA-NTRK1 rearrangement within chromosome 1 with oncogenic potential, and the patient was treated with the pan-TRK inhibitor entrectinib, achieving partial response with decrease in hepatic target lesions from 6.8 and 8.2cm in longest diameter to 4.7 and 4.3cm, respectively. To our knowledge, this is the first clinical evidence of efficacy for therapeutic inhibition of TRKA in a solid tumor, illuminating a genomic-driven strategy to identify CRCs reliant on this oncogene to be clinically targeted with entrectinib. Oxford University Press 2015-11-12 /pmc/articles/PMC4712682/ /pubmed/26563355 http://dx.doi.org/10.1093/jnci/djv306 Text en © The Author 2015. Published by Oxford University Press. http://creativecommons.org/licenses/by-nc/4.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Brief Communication
Sartore-Bianchi, Andrea
Ardini, Elena
Bosotti, Roberta
Amatu, Alessio
Valtorta, Emanuele
Somaschini, Alessio
Raddrizzani, Laura
Palmeri, Laura
Banfi, Patrizia
Bonazzina, Erica
Misale, Sandra
Marrapese, Giovanna
Leone, Antonella
Alzani, Rachele
Luo, David
Hornby, Zachary
Lim, Jonathan
Veronese, Silvio
Vanzulli, Angelo
Bardelli, Alberto
Martignoni, Marcella
Davite, Cristina
Galvani, Arturo
Isacchi, Antonella
Siena, Salvatore
Sensitivity to Entrectinib Associated With a Novel LMNA-NTRK1 Gene Fusion in Metastatic Colorectal Cancer
title Sensitivity to Entrectinib Associated With a Novel LMNA-NTRK1 Gene Fusion in Metastatic Colorectal Cancer
title_full Sensitivity to Entrectinib Associated With a Novel LMNA-NTRK1 Gene Fusion in Metastatic Colorectal Cancer
title_fullStr Sensitivity to Entrectinib Associated With a Novel LMNA-NTRK1 Gene Fusion in Metastatic Colorectal Cancer
title_full_unstemmed Sensitivity to Entrectinib Associated With a Novel LMNA-NTRK1 Gene Fusion in Metastatic Colorectal Cancer
title_short Sensitivity to Entrectinib Associated With a Novel LMNA-NTRK1 Gene Fusion in Metastatic Colorectal Cancer
title_sort sensitivity to entrectinib associated with a novel lmna-ntrk1 gene fusion in metastatic colorectal cancer
topic Brief Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712682/
https://www.ncbi.nlm.nih.gov/pubmed/26563355
http://dx.doi.org/10.1093/jnci/djv306
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