A comprehensive clinically informed map of dependencies in cancer cells and framework for target prioritization

Learning and actioning general principles of cancer cell drug sensitivity

“…Overall, 135 GDSC drug models out of 253 can recover either the target or MOA-related pathways among important genes, suggesting that drug-specific models leverage known biological mechanisms to carry out their prediction task. We also demonstrated that the important genes of the model successfully recapitulated cancer tissue essential genes from a recently published compendium (Pacini et al, 2024). Our models’ interpretation clearly suggests that drug sensitivity emerges from the interplay of drug MOAs and genes essential for cell survival.…”

“…In this respect, we retained drug-cell line instances yielding more significant predictions, ranked the top k most important genes based on SHAP values, and pooled them on the basis of the tissue of origin of the cell lines. We then evaluated the recall of the top k important genes to identify core essential genes from an updated dependency map across 27 cancer tissues (Pacini et al, 2024). Depending on how many top k important genes we considered, we were able to recover a variable number of gene dependencies for all the tissues.…”

“…We assessed the potential of local SHAP values, representing gene impacts on drug-cell line pair predictions, to identify genes involved in gene essentiality, as evidenced by CRISPR knock-out screenings. Utilizing a dataset from Pacini et al (Pacini et al, 2024), which lists essential genes across tissues and CRISPR Gene dependencies (see “Datasets”), we tailored this analysis to include only those cell lines and tissues mentioned therein. This required harmonizing tissue nomenclature differences between our dataset and Pacini et al, notably merging Esophagus and Stomach categories into a single group and mapping other tissues’ names to match our dataset’s structure (the mapping will be released together with the code to reproduce the analysis).…”

“…We then evaluated the recall of the top k important genes to identify core essential genes from an updated dependency map across 27 cancer tissues (Pacini et al, 2024). Depending on how many top k important genes we considered, we were able to recover a variable number of gene dependencies for all the tissues.…”

Precision Oncology, Signaling Pathways Reprogramming and Targeted Therapy: A Holistic Approach to Molecular Cancer Therapeutics

“…CRISPR-Cas9 gene editing is an efficient method of modifying the genome of almost any cell type. CRISPR editing and screening have emerged as powerful tools for studying nearly all aspects of cellular behaviors which have greatly influenced our understanding of cancer biology and continue to contribute to new discoveries [17,18]. A related project called Cancer Cell Line Encyclopedia (CCLE), started as a collaboration between the Broad Institute and the Novartis Institute for Biomedical Research in 2008, appears well suited for large-scale genetic characterization of thousands of cancer cell lines in order to link characteristics genetic alterations with distinct pharmacological vulnerabilities, and to translate integrative genomics into patients stratification for personalized cancer treatments.…”