# Synthetic lethality

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

## TL;DR

Two genes where losing either alone is fine but losing both kills the cell. Cancers that have lost one become vulnerable to drugs against the other.

## Summary

Synthetic lethality describes two genes where losing either alone is tolerated but losing both kills the cell, so a cancer that has lost one becomes vulnerable to a drug against the other. BRCA and PARP is the proven pair; others in development include MTAP/PRMT5, MSI/WRN, HRD/POLQ, TP53/WEE1, SMARCA4/SMARCA2 and ARID1A/EZH2, and CRISPR screens map such pairs systematically. The concept links to the Synthetic lethality approaches, PARP inhibitors and CRISPR functional genomics technologies and is cited by the Ovarian cancer and Mesothelioma entries, The Institute of Cancer Research and Christopher Lord. Ideas drawing on it include PRMT5/MAT2A lethality for MTAP-deleted mesothelioma, a WRN inhibitor programme and a synthetic lethality map for every cancer driver.

## Fields

- Kind: Term
- Last checked: 2026-09-04

## Sources

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

## Connected records

- technologies: [CRISPR functional genomics](https://onco.cc/technologies/crispr-screens/), [PARP inhibitors](https://onco.cc/technologies/parp-inhibitor/), [Synthetic lethality approaches](https://onco.cc/technologies/synthetic-lethality-approaches/)
- cancers: [Mesothelioma](https://onco.cc/cancers/mesothelioma/), [Ovarian cancer](https://onco.cc/cancers/ovarian/), [Pancreatic ductal adenocarcinoma](https://onco.cc/cancers/pancreatic/), [Prostate cancer](https://onco.cc/cancers/prostate/), [Triple-negative breast cancer (TNBC)](https://onco.cc/cancers/tnbc/)
- 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/), [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/)
- 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/), [MYC pathway activation in triple-negative breast cancer is synthetic lethal with CDK inhibition](https://onco.cc/key-papers/paper-horiuchi-myc-tnbc-cdk-synthetic-lethal-jem-2012/), [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/), [Phase II study of maintenance rucaparib in patients with platinum-sensitive advanced pancreatic cancer and a pathogenic germline or somatic variant in BRCA1, BRCA2, or PALB2](https://onco.cc/key-papers/paper-reiss-rucaparib-maintenance-brca-palb2-pancreatic-jco-2021/), [POLO: maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer](https://onco.cc/key-papers/paper-polo-olaparib-maintenance-gbrca-pancreatic-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/), [TOPARP-A: DNA-repair defects and olaparib in metastatic prostate cancer](https://onco.cc/key-papers/paper-mateo-toparp-a-olaparib-dna-repair-nejm-2015/), [TRITON2: rucaparib in men with metastatic castration-resistant prostate cancer harbouring a BRCA1 or BRCA2 alteration](https://onco.cc/key-papers/paper-abida-triton2-rucaparib-brca-jco-2020/), [TRITON3: rucaparib or physician's choice in metastatic castration-resistant prostate cancer](https://onco.cc/key-papers/paper-fizazi-triton3-rucaparib-nejm-2023/)
- terms: [Checkpoint (two meanings)](https://onco.cc/terms/checkpoint/), [Deletion](https://onco.cc/terms/deletion/), [Genome-wide loss of heterozygosity (gLOH)](https://onco.cc/terms/genome-wide-loss-of-heterozygosity/), [Somatic mutation theory of cancer](https://onco.cc/terms/somatic-mutation-theory/), [Tumour suppressor gene](https://onco.cc/terms/tumour-suppressor-gene/)
- biomarkers: [Homologous recombination repair gene mutation in prostate cancer](https://onco.cc/biomarkers/hrr-gene-mutation/)
- institutions: [Newcastle Cancer Centre / Northern Centre for Cancer Care](https://onco.cc/institutions/newcastle-cancer-centre/), [The Institute of Cancer Research](https://onco.cc/institutions/icr-london/), [The Wistar Institute](https://onco.cc/institutions/wistar/)
- people: [Christopher Lord](https://onco.cc/people/chris-lord/)
- pathways: [Base excision repair, PARP & alkylation damage](https://onco.cc/pathways/base-excision-repair-parp/), [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/), [Synthetic lethality: paired dependencies](https://onco.cc/pathways/synthetic-lethality-map/)
- targets: [PRMT5 (MTAP-deleted cancers)](https://onco.cc/targets/prmt5-mtap/), [WRN helicase (MSI-high cancers)](https://onco.cc/targets/wrn/)

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