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Acquisition of chromosome instability is a mechanism to evade oncogene addiction

Chromosome instability (CIN) has been associated with therapeutic resistance in many cancers. However, whether tumours become genomically unstable as an evolutionary mechanism to overcome the bottleneck exerted by therapy is not clear. Using a CIN model of Kras‐driven breast cancer, we demonstrate t...

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Autores principales: Salgueiro, Lorena, Buccitelli, Christopher, Rowald, Konstantina, Somogyi, Kalman, Kandala, Sridhar, Korbel, Jan O, Sotillo, Rocio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059010/
https://www.ncbi.nlm.nih.gov/pubmed/32030896
http://dx.doi.org/10.15252/emmm.201910941
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author Salgueiro, Lorena
Buccitelli, Christopher
Rowald, Konstantina
Somogyi, Kalman
Kandala, Sridhar
Korbel, Jan O
Sotillo, Rocio
author_facet Salgueiro, Lorena
Buccitelli, Christopher
Rowald, Konstantina
Somogyi, Kalman
Kandala, Sridhar
Korbel, Jan O
Sotillo, Rocio
author_sort Salgueiro, Lorena
collection PubMed
description Chromosome instability (CIN) has been associated with therapeutic resistance in many cancers. However, whether tumours become genomically unstable as an evolutionary mechanism to overcome the bottleneck exerted by therapy is not clear. Using a CIN model of Kras‐driven breast cancer, we demonstrate that aneuploid tumours acquire genetic modifications that facilitate the development of resistance to targeted therapy faster than euploid tumours. We further show that the few initially chromosomally stable cancers that manage to persist during treatment do so concomitantly with the acquisition of CIN. Whole‐genome sequencing analysis revealed that the most predominant genetic alteration in resistant tumours, originated from either euploid or aneuploid primary tumours, was an amplification on chromosome 6 containing the cMet oncogene. We further show that these tumours are dependent on cMet since its pharmacological inhibition leads to reduced growth and increased cell death. Our results highlight that irrespective of the initial CIN levels, cancer genomes are dynamic and the acquisition of a certain level of CIN, either induced or spontaneous, is a mechanism to circumvent oncogene addiction.
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spelling pubmed-70590102020-03-11 Acquisition of chromosome instability is a mechanism to evade oncogene addiction Salgueiro, Lorena Buccitelli, Christopher Rowald, Konstantina Somogyi, Kalman Kandala, Sridhar Korbel, Jan O Sotillo, Rocio EMBO Mol Med Articles Chromosome instability (CIN) has been associated with therapeutic resistance in many cancers. However, whether tumours become genomically unstable as an evolutionary mechanism to overcome the bottleneck exerted by therapy is not clear. Using a CIN model of Kras‐driven breast cancer, we demonstrate that aneuploid tumours acquire genetic modifications that facilitate the development of resistance to targeted therapy faster than euploid tumours. We further show that the few initially chromosomally stable cancers that manage to persist during treatment do so concomitantly with the acquisition of CIN. Whole‐genome sequencing analysis revealed that the most predominant genetic alteration in resistant tumours, originated from either euploid or aneuploid primary tumours, was an amplification on chromosome 6 containing the cMet oncogene. We further show that these tumours are dependent on cMet since its pharmacological inhibition leads to reduced growth and increased cell death. Our results highlight that irrespective of the initial CIN levels, cancer genomes are dynamic and the acquisition of a certain level of CIN, either induced or spontaneous, is a mechanism to circumvent oncogene addiction. John Wiley and Sons Inc. 2020-02-06 2020-03-06 /pmc/articles/PMC7059010/ /pubmed/32030896 http://dx.doi.org/10.15252/emmm.201910941 Text en © 2020 The Authors. Published under the terms of the CC BY 4.0 license. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
Salgueiro, Lorena
Buccitelli, Christopher
Rowald, Konstantina
Somogyi, Kalman
Kandala, Sridhar
Korbel, Jan O
Sotillo, Rocio
Acquisition of chromosome instability is a mechanism to evade oncogene addiction
title Acquisition of chromosome instability is a mechanism to evade oncogene addiction
title_full Acquisition of chromosome instability is a mechanism to evade oncogene addiction
title_fullStr Acquisition of chromosome instability is a mechanism to evade oncogene addiction
title_full_unstemmed Acquisition of chromosome instability is a mechanism to evade oncogene addiction
title_short Acquisition of chromosome instability is a mechanism to evade oncogene addiction
title_sort acquisition of chromosome instability is a mechanism to evade oncogene addiction
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059010/
https://www.ncbi.nlm.nih.gov/pubmed/32030896
http://dx.doi.org/10.15252/emmm.201910941
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