# Synthetic lethality approaches

Source: https://onco.cc/technologies/synthetic-lethality-approaches/  
OnCo record `synthetic-lethality-approaches` (Technology). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Finding a second gene that a cancer needs only because its first gene is broken, then hitting the second one.

## Summary

PARP inhibition in BRCA loss is the proven case. Next: PRMT5 inhibitors (MTAP-deleted tumours, ~15% of cancers; AMG 193, MRTX1719 in phase 2/3), WRN inhibitors (MSI-high), POLQ inhibitors (HRD), and WEE1/ATR in TP53-mutant and CCNE1-amplified tumours. CRISPR screens (DepMap) systematically map these dependencies.

## Fields

- Kind: Technology
- Status: approved
- Last checked: 2026-09-04
- Principle: Genetic interaction where loss of both genes, but neither alone, is lethal.
- Strengths: Targets tumour-suppressor loss, which conventional drugs cannot; Large therapeutic window
- Limitations: Context dependence; resistance via reversion

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Synthetic_lethality
- Wikipedia: https://en.wikipedia.org/wiki/Synthetic_lethality

## Connected records

- fronts: [Drug Discovery Platforms](https://onco.cc/fronts/drug-discovery/), [Targeted Therapy](https://onco.cc/fronts/targeted-therapy/)
- targets: [ATR](https://onco.cc/targets/atr/), [BRCA1 / BRCA2 (HRD)](https://onco.cc/targets/brca/), [PARP](https://onco.cc/targets/parp/), [PRMT5 (MTAP-deleted cancers)](https://onco.cc/targets/prmt5-mtap/), [TP53](https://onco.cc/targets/tp53/), [WEE1](https://onco.cc/targets/wee1/), [WRN helicase (MSI-high cancers)](https://onco.cc/targets/wrn/)
- companies: [Amphista Therapeutics](https://onco.cc/companies/amphista-therapeutics/), [Debiopharm](https://onco.cc/companies/debiopharm/), [Foghorn Therapeutics](https://onco.cc/companies/foghorn-therapeutics/), [IDEAYA Biosciences](https://onco.cc/companies/ideaya-biosciences/), [Nimbus Therapeutics](https://onco.cc/companies/nimbus-therapeutics/), [Plexium](https://onco.cc/companies/plexium/), [Repare Therapeutics](https://onco.cc/companies/repare-therapeutics/), [Tango Therapeutics](https://onco.cc/companies/tango-therapeutics/)
- terms: [Synthetic lethality](https://onco.cc/terms/synthetic-lethality/)
- cancers: [Mesothelioma](https://onco.cc/cancers/mesothelioma/), [Ovarian cancer](https://onco.cc/cancers/ovarian/)
- ideas: [A synthetic lethality map for every cancer driver in every tissue context](https://onco.cc/ideas/idea-moon-synthetic-lethality-map-every-driver/), [Attack the backup copy when a tumour has lost the original gene](https://onco.cc/ideas/idea-bio1-paralog-synthetic-lethality/), [Group trials by broken mechanism, not by organ or single mutation](https://onco.cc/ideas/idea-bio2-mechanism-defined-baskets/), [Kill the sleeping survivor cells with iron-dependent cell death](https://onco.cc/ideas/idea-bio1-persister-ferroptosis/), [PRMT5/MAT2A synthetic lethality for MTAP-deleted mesothelioma](https://onco.cc/ideas/idea-mtap-prmt5-mesothelioma/), [Turn chromosomal chaos into a weakness with KIF18A inhibitors](https://onco.cc/ideas/idea-bio1-cin-vulnerability-kif18a/), [WRN inhibitors: a second synthetic-lethal win for mismatch-repair cancers](https://onco.cc/ideas/idea-bio1-wrn-msi-programme/)
- technologies: [ATR and CHK1 inhibitors](https://onco.cc/technologies/atr-chk1-inhibitors/), [Cancer cell line encyclopedias and dependency maps](https://onco.cc/technologies/cancer-cell-line-encyclopedias/), [CRISPR functional genomics](https://onco.cc/technologies/crispr-screens/), [High-throughput screening and DNA-encoded libraries](https://onco.cc/technologies/high-throughput-screening-libraries/), [Metabolic therapy: starving the tumour of a nutrient](https://onco.cc/technologies/metabolic-therapy/)
- institutions: [Broad Institute of MIT and Harvard](https://onco.cc/institutions/broad-institute/), [Newcastle Cancer Centre / Northern Centre for Cancer Care](https://onco.cc/institutions/newcastle-cancer-centre/)
- pathways: [DNA damage response & homologous recombination](https://onco.cc/pathways/ddr/), [DNA replication stress](https://onco.cc/pathways/replication-stress/), [Double-strand break repair: HR versus end joining](https://onco.cc/pathways/homologous-recombination-repair/), [Drivers, passengers & the two-hit model](https://onco.cc/pathways/oncogene-activation-two-hit/), [Mismatch repair & microsatellite instability](https://onco.cc/pathways/mismatch-repair-msi/), [SWI/SNF chromatin remodelling](https://onco.cc/pathways/swi-snf-chromatin/), [Synthetic lethality: paired dependencies](https://onco.cc/pathways/synthetic-lethality-map/), [The p53 network (guardian of the genome)](https://onco.cc/pathways/p53-mdm2-axis/)
- collections: [DepMap (Cancer Dependency Map)](https://onco.cc/collections/depmap/)
- people: [Alan Ashworth](https://onco.cc/people/alan-ashworth/), [Alan D. D'Andrea](https://onco.cc/people/alan-dandrea/), [Christopher Lord](https://onco.cc/people/chris-lord/), [Francisca Vazquez](https://onco.cc/people/francisca-vazquez/), [Thomas Helleday](https://onco.cc/people/thomas-helleday/)
- bottlenecks: [The undruggable drivers](https://onco.cc/bottlenecks/b-undruggable-targets/)
- key papers: [Defining a Cancer Dependency Map: which genes each cancer cell line cannot live without](https://onco.cc/key-papers/paper-depmap-tsherniak-cell-2017/), [OlympiA: a year of olaparib after surgery for BRCA-mutated, high-risk early breast cancer](https://onco.cc/key-papers/paper-olympia-nejm-2021/), [PAOLA-1: olaparib added to bevacizumab maintenance in newly diagnosed ovarian cancer, with benefit confined to HRD-positive tumours](https://onco.cc/key-papers/paper-paola-1-nejm-2019/), [SOLO-1: two years of olaparib maintenance after first-line chemotherapy for BRCA-mutated ovarian cancer](https://onco.cc/key-papers/paper-solo-1-nejm-2018/)
- roadmaps: [Drug discovery roadmap: screening in mice → maps of dependency → designing in silico](https://onco.cc/roadmaps/drug-discovery-roadmap/), [Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall](https://onco.cc/roadmaps/targeted-therapy-roadmap/)

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