Analysis of Cancer Genomic Amplifications Identifies Druggable Collateral Dependencies within the Amplicon

Simple Summary Genomic amplifications are highly prevalent in cancer and often contribute to increased proliferation or cell survival upon the administration of anti-cancer drugs. The identification of those amplified genes at which cancer cells are selectively dependent is crucial for the developme...

ver descrição completa

Detalhes bibliográficos
Autores: Pons, G, Gallo-Oller, G, Navarro, N, Zarzosa, P, Sansa-Girona, J, García-Gilabert, L, Magdaleno, A, Segura, MF, de Toledo, JS, Gallego, S, Moreno, L, Roma, J
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2023
País:España
Recursos:Fundació Sant Joan de Déu
Repositorio:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
OAI Identifier:oai:fsjd.fundanetsuite.com:p28164
Acesso em linha:https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=28164
Access Level:acceso abierto
Palavra-chave:cancer
gene amplifications
CRISPR-Cas9 screenings
gene dependencies
drug development
id ES_bf746ae590d554dbbd76e54827e10928
oai_identifier_str oai:fsjd.fundanetsuite.com:p28164
network_acronym_str ES
network_name_str España
repository_id_str
spelling Analysis of Cancer Genomic Amplifications Identifies Druggable Collateral Dependencies within the AmpliconPons, GGallo-Oller, GNavarro, NZarzosa, PSansa-Girona, JGarcía-Gilabert, LMagdaleno, ASegura, MFde Toledo, JSGallego, SMoreno, LRoma, Jcancergene amplificationsCRISPR-Cas9 screeningsgene dependenciesdrug developmentSimple Summary Genomic amplifications are highly prevalent in cancer and often contribute to increased proliferation or cell survival upon the administration of anti-cancer drugs. The identification of those amplified genes at which cancer cells are selectively dependent is crucial for the development of new targeted therapies. On this matter, CRISPR/Cas9 screens have emerged as a useful tool to deplete the expression of almost all genes while assessing their consequences for cell survival. Here, we analyzed data from CRISPR/Cas9 screens in 954 cancer cell lines to identify selective gene dependencies associated with common cancer genomic amplifications. Our results suggest that cell lines of different tumor types harboring the same genomic amplification are dependent almost entirely on the same amplified genes, providing a set of new promising targets specific to each genomic amplification. The identification of novel therapeutic targets for specific cancer molecular subtypes is crucial for the development of precision oncology. In the last few years, CRISPR/Cas9 screens have accelerated the discovery and validation of new targets associated with different tumor types, mutations, and fusions. However, there are still many cancer vulnerabilities associated with specific molecular features that remain to be explored. Here, we used data from CRISPR/Cas9 screens in 954 cancer cell lines to identify gene dependencies associated with 16 common cancer genomic amplifications. We found that high-copy-number genomic amplifications generate multiple collateral dependencies within the amplified region in most cases. Further, to prioritize candidate targets for each chromosomal region amplified, we integrated gene dependency parameters with both druggability data and subcellular location. Finally, analysis of the relationship between gene expression and gene dependency led to the identification of genes, the expression of which may constitute predictive biomarkers of dependency. In conclusion, our study provides a set of druggable targets specific for each amplification, opening the possibility to specifically target amplified tumors on this basis.MDPI2023info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=28164CancersISSN: 20726694reponame:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déuinstname:Fundació Sant Joan de DéuInglésinfo:eu-repo/semantics/openAccessoai:fsjd.fundanetsuite.com:p281642026-05-27T12:37:41Z
dc.title.none.fl_str_mv Analysis of Cancer Genomic Amplifications Identifies Druggable Collateral Dependencies within the Amplicon
title Analysis of Cancer Genomic Amplifications Identifies Druggable Collateral Dependencies within the Amplicon
spellingShingle Analysis of Cancer Genomic Amplifications Identifies Druggable Collateral Dependencies within the Amplicon
Pons, G
cancer
gene amplifications
CRISPR-Cas9 screenings
gene dependencies
drug development
title_short Analysis of Cancer Genomic Amplifications Identifies Druggable Collateral Dependencies within the Amplicon
title_full Analysis of Cancer Genomic Amplifications Identifies Druggable Collateral Dependencies within the Amplicon
title_fullStr Analysis of Cancer Genomic Amplifications Identifies Druggable Collateral Dependencies within the Amplicon
title_full_unstemmed Analysis of Cancer Genomic Amplifications Identifies Druggable Collateral Dependencies within the Amplicon
title_sort Analysis of Cancer Genomic Amplifications Identifies Druggable Collateral Dependencies within the Amplicon
dc.creator.none.fl_str_mv Pons, G
Gallo-Oller, G
Navarro, N
Zarzosa, P
Sansa-Girona, J
García-Gilabert, L
Magdaleno, A
Segura, MF
de Toledo, JS
Gallego, S
Moreno, L
Roma, J
author Pons, G
author_facet Pons, G
Gallo-Oller, G
Navarro, N
Zarzosa, P
Sansa-Girona, J
García-Gilabert, L
Magdaleno, A
Segura, MF
de Toledo, JS
Gallego, S
Moreno, L
Roma, J
author_role author
author2 Gallo-Oller, G
Navarro, N
Zarzosa, P
Sansa-Girona, J
García-Gilabert, L
Magdaleno, A
Segura, MF
de Toledo, JS
Gallego, S
Moreno, L
Roma, J
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv cancer
gene amplifications
CRISPR-Cas9 screenings
gene dependencies
drug development
topic cancer
gene amplifications
CRISPR-Cas9 screenings
gene dependencies
drug development
description Simple Summary Genomic amplifications are highly prevalent in cancer and often contribute to increased proliferation or cell survival upon the administration of anti-cancer drugs. The identification of those amplified genes at which cancer cells are selectively dependent is crucial for the development of new targeted therapies. On this matter, CRISPR/Cas9 screens have emerged as a useful tool to deplete the expression of almost all genes while assessing their consequences for cell survival. Here, we analyzed data from CRISPR/Cas9 screens in 954 cancer cell lines to identify selective gene dependencies associated with common cancer genomic amplifications. Our results suggest that cell lines of different tumor types harboring the same genomic amplification are dependent almost entirely on the same amplified genes, providing a set of new promising targets specific to each genomic amplification. The identification of novel therapeutic targets for specific cancer molecular subtypes is crucial for the development of precision oncology. In the last few years, CRISPR/Cas9 screens have accelerated the discovery and validation of new targets associated with different tumor types, mutations, and fusions. However, there are still many cancer vulnerabilities associated with specific molecular features that remain to be explored. Here, we used data from CRISPR/Cas9 screens in 954 cancer cell lines to identify gene dependencies associated with 16 common cancer genomic amplifications. We found that high-copy-number genomic amplifications generate multiple collateral dependencies within the amplified region in most cases. Further, to prioritize candidate targets for each chromosomal region amplified, we integrated gene dependency parameters with both druggability data and subcellular location. Finally, analysis of the relationship between gene expression and gene dependency led to the identification of genes, the expression of which may constitute predictive biomarkers of dependency. In conclusion, our study provides a set of druggable targets specific for each amplification, opening the possibility to specifically target amplified tumors on this basis.
publishDate 2023
dc.date.none.fl_str_mv 2023
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=28164
url https://fsjd.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=28164
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv Cancers
ISSN: 20726694
reponame:r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
instname:Fundació Sant Joan de Déu
instname_str Fundació Sant Joan de Déu
reponame_str r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
collection r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869418392651300864
score 15.81155

Registos relacionados