publications

2026

1. 

   Systematic prioritisation of context-specific paralog pair vulnerabilities in cancer

   Narod Daldal, Hamda Ajmal, David J Adams, and 1 more author

   Genome Medicine, Sep 2026

   Abs DOI

   Background Genome-wide CRISPR screening has enabled the development of dependency maps in hundreds of cancer cell lines, facilitating the identification of genetic vulnerabilities associated with specific biomarkers and supporting precision oncology efforts. However, current dependency maps largely capture single-gene effects and systematically miss vulnerabilities where functional compensation between paralogs masks the underlying dependency. Combinatorial screens have revealed that paralog pairs are often synthetic lethal but that these effects are highly context-dependent across tumour types and genetic backgrounds. To enable the clinical translation of paralog synthetic lethality, it is therefore necessary to identify which paralog pairs constitute actionable vulnerabilities in specific cancer contexts.
   
   Methods We developed a machine learning classifier to predict cell-line-specific synthetic lethality between paralog pairs using features derived from transcriptomics, genomics, gene essentiality, and network context. We designed an evaluation framework spanning three biologically relevant scenarios: predicting synthetic lethality for seen paralog pairs in unseen cell lines, for unseen pairs in seen cell lines, and for unseen pairs in unseen cell lines. We applied the model to 33,419 pairs across 1,005 cancer cell lines and validated predictions using independent combinatorial CRISPR screens.
   
   Results We found that the cell-line-specific expression and essentiality of paralogs and their interaction partners are informative for predicting synthetic lethal interactions. Our model generalised to unseen paralog pairs and to unseen cell lines, though the combination of both was the most challenging scenario. The agreement between predicted and experimentally observed interactions was comparable to that between independent experimental studies, suggesting that predictive accuracy may be constrained as much by experimental reproducibility as by the model itself. When applied to HER2-amplified breast cancer, the model recovered known synergies and predicted novel biomarker-associated vulnerabilities.
   
   Conclusions We present a comprehensive, context-resolved resource of paralog synthetic lethal vulnerabilities across 1,005 cancer cell lines. This resource enables systematic, disease-stratified prioritisation of paralog-pair dependencies. Genome-scale predictions are made available through an interactive web portal (https://cancergenetics.github.io/paralogmap/) to support hypothesis generation, guide targeted combinatorial screening, and facilitate the identification of clinically actionable paralog targets.

2025

1. 

   A compendium of synthetic lethal gene pairs defined by extensive combinatorial pan-cancer CRISPR screening

   Victoria Harle, Victoria Offord, Birkan Gökbağ, and 15 more authors

   Genome Biol., Sep 2025

   Abs DOI

   Background Synthetic lethal interactions are attractive therapeutic candidates as they enable selective targeting of cancer cells in which somatic alterations have disrupted one member of a synthetic lethal gene pair while leaving normal tissues untouched, thus minimising off-target toxicity. Despite this potential, the number of well-established and validated synthetic lethal gene pairs is modest.
   
   Results We generate a dual-guide CRISPR/Cas9 Library and analyse 472 predicted synthetic lethal pairs in 27 cancer cell Lines from melanoma, pancreatic and lung cancer Lineages. We report a robust collection of 117 genetic interactions within and across cancer types and explore their candidacy as therapeutic targets. We show that SLC25A28 is an attractive target since its synthetic lethal paralog partner SLC25A37 is homozygously deleted pan-cancer. We generate knockout mice for Slc25a28 revealing that, except for cataracts in some mice, these animals are normal; suggesting inhibition of SLC25A28 is unlikely to be associated with profound toxicity.
   
   Conclusions We provide and validate an extensive collection of synthetic lethal interactions across cancer types.

2. 

   Benchmarking genetic interaction scoring methods for identifying synthetic lethality from combinatorial CRISPR screens

   Hamda Ajmal, Sutanu Nandi, Narod Kebabci, and 1 more author

   NAR Genom. Bioinform., Sep 2025

   Abs DOI

   Synthetic lethality (SL) is an extreme form of negative genetic interaction, where simultaneous disruption of two non-essential genes causes cell death. SL can be exploited to develop cancer therapies that target tumour cells with specific mutations, potentially limiting toxicity. Pooled combinatorial CRISPR screens, where two genes are simultaneously perturbed and the resulting impacts on fitness estimated, are now widely used for the identification of SL targets in cancer. Various scoring methods have been developed to infer SL genetic interactions from these screens, but there has been no systematic comparison of these approaches. Here, we performed a comprehensive analysis of five scoring methods for SL detection using five combinatorial CRISPR datasets. We assessed the performance of each algorithm on each screen dataset using two different benchmarks of paralog SL. We find that no single method performs best across all screens but identify two methods that perform well across most datasets. Of these two scores, Gemini-Sensitive has an available R package that can be applied to most screen designs, making it a reasonable first choice.

2023

1. 

   Targeting synthetic lethal paralogs in cancer

   Colm J Ryan, Ishan Mehta, Narod Kebabci, and 1 more author

   Trends Cancer, May 2023

   Abs DOI

   Synthetic lethal interactions, where mutation of one gene renders cells sensitive to inhibition of another gene, can be exploited for the development of targeted therapeutics in cancer. Pairs of duplicate genes (paralogs) often share common functionality and hence are a potentially rich source of synthetic lethal interactions. Because the majority of human genes have paralogs, exploiting such interactions could be a widely applicable approach for targeting gene loss in cancer. Moreover, existing small-molecule drugs may exploit synthetic lethal interactions by inhibiting multiple paralogs simultaneously. Consequently, the identification of synthetic lethal interactions between paralogs could be extremely informative for drug development. Here we review approaches to identify such interactions and discuss some of the challenges of exploiting them.

2022

1. 

   Toward compilation of balanced protein stability data sets: Flattening the ΔΔG curve through systematic enrichment

   Narod Kebabci, Ahmet Can Timucin, and Emel Timucin

   J. Chem. Inf. Model., Mar 2022

   Abs DOI

   Often studies analyzing stability data sets and/or predictors ignore neutral mutations and use a binary classification scheme labeling only destabilizing and stabilizing mutations. Recognizing that highly concentrated neutral mutations interfere with data set quality, we have explored three protein stability data sets: S2648, PON-tstab, and the symmetric Ssym that differ in size and quality. A characteristic leptokurtic shape in the ΔΔG distributions of all three data sets including the curated and symmetric ones was reported due to concentrated neutral mutations. To further investigate the impact of neutral mutations on ΔΔG predictions, we have comprehensively assessed the performance of 11 predictors on the PON-tstab data set. Correlation and error analyses showed that all of the predictors performed the best on the neutral mutations, while their performance became gradually worse as the ΔΔG of the mutations departed further from the neutral zone regardless of the direction, implying a bias toward dense mutations. To this end, after unraveling the role of concentrated neutral mutations in biases of stability data sets, we described a systematic enrichment approach to balance the ΔΔG distributions. Before enrichment, mutations were clustered based on their biochemical and/or structural features, and then three mutations were selected from every 2 kcal/mol of each cluster. Upon implementation of this approach by distinct clustering schemes, we generated five subsets varying in size and ΔΔG distributions. All subsets showed improved ΔΔG and frequency distributions. We ultimately reported that the errors toward enriched subsets were higher than those toward the parent data sets, confirming the enrichment of difficult-to-predict mutations in the subsets. In summary, we elaborated the prediction bias toward a concentrated neutral zone and also implemented a rational strategy to tackle this and other forms of biases. Ultimately, this study equipping us with an extended view of shortcomings of stability data sets is a step taken toward development of an unbiased predictor.