Based on these efforts, recently the Werner syndrome helicase (WRN) was found as a promising SL target in microsatellite instable cancers. In addition, prioritization of cancer therapeutic targets has been proposed based on a priority score derived from experimental evidence, the significance of fitness deficiency, target gene expression, target mutational status and evidence for other fitness genes in the same pathway. For instance, data from the Achilles project (part of the DepMap consortium ), based on both CRISPR-Cas9 and shRNA screens, have been exploited to uncover new potential SL interactions and several computational approaches have been developed for this purpose.
This includes CRISPR/Cas9-based KO screens, RNAi and drug screens together with gene expression, mutation and copy number variation data. Studies in human cancer cell lines have accumulated multiple layers of genetic information that can be used to study SL interactions. This discovery promoted the search for additional synthetic lethal (SL) targets in cancer research. The first successful therapy based on this approach is the use of Poly-ADP-ribose polymerase 1 (PARP1) inhibitors in patients deficient in homologous recombination pathway. This phenomenon, first described in Drosophila melanogaster, has been used as an approach in cancer therapy to exploit vulnerabilities of cancer cells by identifying druggable targets that when ablated or inhibited would selectively impact the viability of aberrant cancer cells. The PARIS pipeline repository is available at, it includes the main functions to run PARIS as well as the ones used to perform the analysis and to generate the plots in the present work.Ĭorrespondence and requests for materials should be addressed to B.R.M lethality occurs when simultaneous perturbation in two or more genes leads to cell death, whereas individual inactivation of single genes is still compatible with cell survival. 10 g and h are provided as Additional file 4. 3d is provided as source Additional file 2. The R shiny apps showing the preprocessed PARIS results can be downloaded at and at and run on a local computer. GUID: A76F5033-2780-476E-8375-630A77F8097E Data Availability StatementĪll data associated with this study are presented in the paper and DepMap data were downloaded from (version DepMap19Q3). The Creative Commons Public Domain Dedication waiver ( ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
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