Pathway-driven analysis of synthetic lethal interactions in cancer using perturbation screens

Abstract

Synthetic lethality offers a promising approach for developing effective therapeutic interventions in cancer when direct targeting of driver genes is impractical. In this study, we comprehensively analyzed large-scale CRISPR, shRNA, and PRISM screens to identify potential synthetic lethal (SL) interactions in pan-cancer and 12 individual cancer types, using a new computational framework that leverages the biological function and signaling pathway information of key driver genes to mitigate the confounding effects of background genetic alterations in different cancer cell lines. This approach has successfully identified several putative SL interactions, includingKRAS-MAP3K2andAPC-TCF7L2in pan cancer, andCCND1-METTL1,TP53-FRS3,SMO-MDM2, andCCNE1-MTORin liver, blood, skin, and gastric cancers, respectively. In addition, we proposed several FDA-approved cancer-targeted drugs for various cancer types through PRISM drug screens, such as cabazitaxel forVHL-mutated kidney cancer and alectinib for lung cancer withNRASorKRASmutations. Leveraging pathway information can enhance the concordance of shRNA and CRISPR screens and provide clinically relevant findings such as the potential efficacy of dasatinib, an inhibitor ofSRC, for colorectal cancer patients with mutations in the WNT signaling pathway. These analyses revealed that taking signaling pathway information into account results in the identification of more promising SL interactions.

The biological essence of synthetic lethality: Bringing new opportunities for cancer therapy

“…The SLIs revealed in cancer cell lines or mouse models may not be reproducible in actual tumor tissues due to heterogeneity or microenvironmental factors. [293][294][295] More rigorous validation using patient-derived organoids and PDX models is required. Besides, off-target toxicity and lack of biomarker-based patient stratification hamper successful clinical application.…”

“…First, the clinical translation efficiency of SL targets and drug candidates identified by high‐throughput screens is still relatively low. The SLIs revealed in cancer cell lines or mouse models may not be reproducible in actual tumor tissues due to heterogeneity or microenvironmental factors 293–295 . More rigorous validation using patient‐derived organoids and PDX models is required.…”