{"entity":{"id":"synthetic-lethality-map","kind":"pathway","name":"Synthetic lethality: paired dependencies","aka":[],"tldr":"Two genes are synthetically lethal when losing either alone is fine but losing both kills the cell. Cancers that have already lost one (a tumour suppressor you cannot put back) become uniquely dependent on the other, which you can drug. BRCA and PARP was the first proof; a dozen more pairs are now in trials.","summary":"Genome-wide CRISPR screens (DepMap, Project Score) and clinical experience have mapped paired dependencies: BRCA1/2 or HRD → PARP1 and POLQ; ATM loss → ATR; TP53 loss or CCNE1 amplification → WEE1 and PKMYT1; MSI-H → WRN helicase; MTAP deletion (co-deleted with CDKN2A in ~15% of cancers) → PRMT5 and MAT2A (MTA-cooperative PRMT5 inhibitors AMG 193, MRTX1719); SMARCA4 loss → SMARCA2 (degraders); ARID1A loss → EZH2 and ATR; RB1 loss → Aurora kinase; VHL loss → HIF-2α (belzutifan is an oncogene-addiction-style version); KRAS mutation → SHP2, SOS1 (collateral dependencies). The concept also covers 'collateral lethality' (passenger deletions removing a paralogue) and 'induced essentiality' under therapy. Clinical success requires a clean biomarker, a selective inhibitor with a therapeutic window (PARP2 and marrow; PRMT5 in normal cells), and tolerance for resistance via restoration of the lost pathway (BRCA reversion) or loss of the dependency (53BP1).","asOf":"2026-09-09","wikipedia":"https://en.wikipedia.org/wiki/Synthetic_lethality","links":[{"label":"Lord & Ashworth, PARP inhibitors: synthetic lethality in the clinic (Science 2017)","url":"https://doi.org/10.1126/science.aam7344"},{"label":"DepMap portal (Broad Institute)","url":"https://depmap.org/portal/"}],"tags":["mechanism","mechanics-atlas"],"related":[],"cancers":[],"sections":[],"technologies":["synthetic-lethality-approaches","crispr-screens","parp-inhibitor","hrd-testing","cgp","functional-drug-testing"],"targets":["parp","brca","wee1","atr","wrn","prmt5-mtap","tp53","hif2a","ezh2"],"drugs":["olaparib","niraparib","talazoparib","belzutifan"],"companies":[],"institutions":[],"pathways":["ddr","homologous-recombination-repair","mismatch-repair-msi","replication-stress","p53-mdm2-axis","hif-vhl"],"terms":["synthetic-lethality","hrd","msi","oncogene-addiction"],"trials":[],"people":[],"bottlenecks":["b-undruggable-targets"],"keyPapers":["paper-lord-science"],"journals":[],"dependsOn":[],"notes":[],"analogy":"A building held up by two pillars. Knock one out and it still stands; nobody notices. But a tumour has already lost one pillar to get where it is, so the second pillar, harmless to attack in every normal cell, brings the whole tumour down when it goes.","nodes":[{"id":"brca","label":"BRCA / HRD loss","x":12,"y":10,"targetId":"brca"},{"id":"parp","label":"→ PARP1, POLQ","x":40,"y":10,"targetId":"parp"},{"id":"p53","label":"TP53 loss, CCNE1 amp","x":12,"y":32,"targetId":"tp53"},{"id":"wee1","label":"→ WEE1, PKMYT1, ATR","x":40,"y":32,"targetId":"wee1"},{"id":"msi","label":"MSI-H (MMR loss)","x":12,"y":54},{"id":"wrn","label":"→ WRN helicase","x":40,"y":54,"targetId":"wrn"},{"id":"mtap","label":"MTAP deletion","x":12,"y":76},{"id":"prmt5","label":"→ PRMT5, MAT2A","x":40,"y":76,"targetId":"prmt5-mtap"},{"id":"atm","label":"ATM loss","x":12,"y":96},{"id":"atr","label":"→ ATR","x":40,"y":96,"targetId":"atr"},{"id":"screen","label":"CRISPR screens (DepMap)","x":78,"y":20},{"id":"drug","label":"Selective inhibitor","x":78,"y":52},{"id":"res","label":"Resistance: restore lost path","x":78,"y":84}],"edges":[{"from":"brca","to":"parp","type":"activates"},{"from":"p53","to":"wee1","type":"activates"},{"from":"msi","to":"wrn","type":"activates"},{"from":"mtap","to":"prmt5","type":"activates"},{"from":"atm","to":"atr","type":"activates"},{"from":"screen","to":"drug","type":"activates"},{"from":"drug","to":"parp","type":"inhibits"},{"from":"drug","to":"wee1","type":"inhibits"},{"from":"drug","to":"wrn","type":"inhibits"},{"from":"drug","to":"prmt5","type":"inhibits"},{"from":"res","to":"drug","type":"inhibits"}],"interventions":["PARP inhibitors for BRCA/HRD (approved in four cancers)","MTA-cooperative PRMT5 inhibitors for MTAP-deleted tumours (mesothelioma, NSCLC, pancreatic; phase 1-2)","WEE1 (azenosertib), PKMYT1 (lunresertib) and ATR (ceralasertib, camonsertib) inhibitors in TP53-mutant, CCNE1-amplified and ATM-deficient tumours","WRN inhibitors for MSI-H; SMARCA2 degraders for SMARCA4-deficient cancers"]},"route":"/pathways/synthetic-lethality-map/","neighbours":{"technology":[{"id":"cgp","kind":"technology","name":"Comprehensive genomic profiling","route":"/technologies/cgp/"},{"id":"crispr-screens","kind":"technology","name":"CRISPR functional genomics","route":"/technologies/crispr-screens/"},{"id":"functional-drug-testing","kind":"technology","name":"Functional (ex vivo) drug testing","route":"/technologies/functional-drug-testing/"},{"id":"hrd-testing","kind":"technology","name":"HRD & BRCA testing","route":"/technologies/hrd-testing/"},{"id":"parp-inhibitor","kind":"technology","name":"PARP inhibitors","route":"/technologies/parp-inhibitor/"},{"id":"synthetic-lethality-approaches","kind":"technology","name":"Synthetic lethality approaches","route":"/technologies/synthetic-lethality-approaches/"}],"target":[{"id":"atm","kind":"target","name":"ATM","route":"/targets/atm/"},{"id":"atr","kind":"target","name":"ATR","route":"/targets/atr/"},{"id":"brca","kind":"target","name":"BRCA1 / BRCA2 (HRD)","route":"/targets/brca/"},{"id":"ccne1","kind":"target","name":"CCNE1","route":"/targets/ccne1/"},{"id":"ezh2","kind":"target","name":"EZH2","route":"/targets/ezh2/"},{"id":"hif2a","kind":"target","name":"HIF-2α","route":"/targets/hif2a/"},{"id":"parp","kind":"target","name":"PARP","route":"/targets/parp/"},{"id":"polk","kind":"target","name":"POLK","route":"/targets/polk/"},{"id":"polq","kind":"target","name":"POLQ","route":"/targets/polq/"},{"id":"prmt5-mtap","kind":"target","name":"PRMT5 (MTAP-deleted cancers)","route":"/targets/prmt5-mtap/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"},{"id":"wee1","kind":"target","name":"WEE1","route":"/targets/wee1/"},{"id":"wrn","kind":"target","name":"WRN helicase (MSI-high cancers)","route":"/targets/wrn/"}],"drug":[{"id":"belzutifan","kind":"drug","name":"Belzutifan","route":"/drugs/belzutifan/"},{"id":"niraparib","kind":"drug","name":"Niraparib","route":"/drugs/niraparib/"},{"id":"olaparib","kind":"drug","name":"Olaparib","route":"/drugs/olaparib/"},{"id":"talazoparib","kind":"drug","name":"Talazoparib","route":"/drugs/talazoparib/"}],"pathway":[{"id":"ddr","kind":"pathway","name":"DNA damage response & homologous recombination","route":"/pathways/ddr/"},{"id":"replication-stress","kind":"pathway","name":"DNA replication stress","route":"/pathways/replication-stress/"},{"id":"homologous-recombination-repair","kind":"pathway","name":"Double-strand break repair: HR versus end joining","route":"/pathways/homologous-recombination-repair/"},{"id":"mismatch-repair-msi","kind":"pathway","name":"Mismatch repair & microsatellite instability","route":"/pathways/mismatch-repair-msi/"},{"id":"p53-mdm2-axis","kind":"pathway","name":"The p53 network (guardian of the genome)","route":"/pathways/p53-mdm2-axis/"},{"id":"hif-vhl","kind":"pathway","name":"VHL / HIF oxygen sensing","route":"/pathways/hif-vhl/"}],"term":[{"id":"hrd","kind":"term","name":"Homologous recombination deficiency (HRD)","route":"/terms/hrd/"},{"id":"msi","kind":"term","name":"Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)","route":"/terms/msi/"},{"id":"oncogene-addiction","kind":"term","name":"Oncogene addiction","route":"/terms/oncogene-addiction/"},{"id":"synthetic-lethality","kind":"term","name":"Synthetic lethality","route":"/terms/synthetic-lethality/"}],"bottleneck":[{"id":"b-undruggable-targets","kind":"bottleneck","name":"The undruggable drivers","route":"/bottlenecks/b-undruggable-targets/"}],"paper":[{"id":"paper-quigley-brca2-reversion-cfdna-parp-resistance-cancer-discov-2017","kind":"paper","name":"Analysis of circulating cell-free DNA identifies multiclonal heterogeneity of BRCA2 reversion mutations associated with resistance to PARP inhibitors","route":"/key-papers/paper-quigley-brca2-reversion-cfdna-parp-resistance-cancer-discov-2017/"},{"id":"paper-horiuchi-myc-tnbc-cdk-synthetic-lethal-jem-2012","kind":"paper","name":"MYC pathway activation in triple-negative breast cancer is synthetic lethal with CDK inhibition","route":"/key-papers/paper-horiuchi-myc-tnbc-cdk-synthetic-lethal-jem-2012/"},{"id":"paper-lord-science","kind":"paper","name":"PARP inhibitors: Synthetic lethality in the clinic","route":"/key-papers/paper-lord-science/"},{"id":"paper-profound-nejm-2020","kind":"paper","name":"PROfound: olaparib for metastatic castration-resistant prostate cancer with homologous recombination repair gene alterations","route":"/key-papers/paper-profound-nejm-2020/"},{"id":"paper-abida-triton2-rucaparib-brca-jco-2020","kind":"paper","name":"TRITON2: rucaparib in men with metastatic castration-resistant prostate cancer harbouring a BRCA1 or BRCA2 alteration","route":"/key-papers/paper-abida-triton2-rucaparib-brca-jco-2020/"}],"cancer":[{"id":"brca-palb2-pdac","kind":"cancer","name":"BRCA or PALB2-mutant pancreatic ductal adenocarcinoma","route":"/cancers/brca-palb2-pdac/"},{"id":"prostate","kind":"cancer","name":"Prostate cancer","route":"/cancers/prostate/"}],"biomarker":[{"id":"hrr-gene-mutation","kind":"biomarker","name":"Homologous recombination repair gene mutation in prostate cancer","route":"/biomarkers/hrr-gene-mutation/"}]}}