TY - JOUR
T1 - Analysis of Cancer Genomic Amplifications Identifies Druggable Collateral Dependencies within the Amplicon
AU - Pons, Guillem
AU - Gallo-Oller, Gabriel
AU - Navarro Barea, Natalia
AU - Zarzosa, Patricia
AU - Sansa-Girona, Júlia
AU - García-Gilabert, Lia
AU - Magdaleno, Ainara
AU - Segura, Miguel F.
AU - Sánchez de Toledo Codin, Josep
AU - Moreno, Lucas
AU - Roma, Josep
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
KW - Cancer
KW - CRISPR-Cas9 screenings
KW - Drug development
KW - Gene dependencies
KW - Gene amplifications
U2 - 10.3390/cancers15061636
DO - 10.3390/cancers15061636
M3 - Article
C2 - 36980521
SN - 2072-6694
VL - 15
JO - Cancers
JF - Cancers
ER -