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

Abstract

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.

Explainable deep learning on 7500 whole genomes elucidates cancer-specific patterns of chromosomal instability

“…An ideal situation is that specific loci define each cancer subtype, thereby directing drug development, and making molecular diagnosis tractable. To date, many cancer-specific CNAs have been identified [13,14] and in specific gene contexts, such as TERT amplifications [15] they can act as biomarkers for disease severity, drug resistance [16], or as novel drug targets [17]. That said, these are often discovered from frequency or mechanistic methodologies and it remains broadly challenging to assess whole cancer genomes for undiscovered loci that are critical to cancer biology.…”