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Updated: Jan 17, 2026
A Data Integration Workflow to Identify Drug Combinations Targeting Synthetic Lethal Interactions
Published on: May 27, 2021
A compendium of synthetic lethal gene pairs defined by extensive combinatorial pan-cancer CRISPR screening
Victoria Harle1, Victoria Offord1, Birkan Gökbağ2
1Wellcome Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
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.
Insights
Researchers identified 117 new synthetic lethal interactions, including targeting SLC25A28, a promising cancer therapy candidate. This discovery offers new strategies for selective cancer cell targeting with minimal toxicity.
Area of Science:
- Genomics
- Cancer Biology
- Drug Discovery
Background:
- Synthetic lethal interactions offer targeted cancer therapy by exploiting genetic differences between cancer and normal cells.
- Current knowledge of validated synthetic lethal gene pairs is limited, hindering therapeutic development.
- Targeting synthetic lethality aims to minimize off-target toxicity in normal tissues.
Purpose of the Study:
- To identify and validate novel synthetic lethal interactions across diverse cancer types.
- To explore the therapeutic potential of newly discovered synthetic lethal gene pairs.
- To assess the safety profile of targeting specific synthetic lethal interactions.
Main Methods:
- Generation of a dual-guide CRISPR/Cas9 library for high-throughput screening.
- Analysis of 472 predicted synthetic lethal pairs in 27 cancer cell lines (melanoma, pancreatic, lung).
- Validation of genetic interactions and assessment of SLC25A28 knockout mouse models.
Main Results:
- A robust collection of 117 genetic interactions was identified within and across cancer types.
- SLC25A28 was highlighted as a potential therapeutic target due to its synthetic lethal partner SLC25A37 being homozygously deleted pan-cancer.
- Slc25a28 knockout mice exhibited minimal toxicity, suggesting SLC25A28 inhibition may be well-tolerated.
Conclusions:
- An extensive and validated collection of synthetic lethal interactions has been established across various cancer types.
- The findings provide a foundation for developing novel, targeted cancer therapies based on synthetic lethality.
- SLC25A28 emerges as a promising target for selective cancer treatment with a potentially favorable safety profile.
