Analysis of Cancer Genomic Amplifications Identifies Druggable Collateral Dependencies within the Amplicon
Pons, Guillem (Hospital Universitari Vall d'Hebron)
Gallo-Oller, Gabriel (Hospital Universitari Vall d'Hebron)
Navarro Barea, Natalia (Hospital Universitari Vall d'Hebron)
Zarzosa, Patricia (Hospital Universitari Vall d'Hebron)
Sansa-Girona, Júlia (Hospital Universitari Vall d'Hebron)
García-Gilabert, Lia (Hospital Universitari Vall d'Hebron)
Magdaleno, Ainara (Hospital Universitari Vall d'Hebron)
Segura, Miguel F. (Hospital Universitari Vall d'Hebron)
Sánchez de Toledo Codin, Josep (Hospital Universitari Vall d'Hebron)
Gallego, Soledad (Hospital Universitari Vall d'Hebron)
Moreno, Lucas (Hospital Universitari Vall d'Hebron)
Roma, Josep (Hospital Universitari Vall d'Hebron)
Universitat Autònoma de Barcelona

Data:	2023
Resum:	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.
Ajuts:	Instituto de Salud Carlos III PI21/00640
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Cancer ; CRISPR-Cas9 screenings ; Drug development ; Gene dependencies ; Gene amplifications
Publicat a:	Cancers, Vol. 15 (march 2023) , ISSN 2072-6694

DOI: 10.3390/cancers15061636
PMID: 36980521

14 p, 2.6 MB

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