{"entity":{"id":"synthetic-lethality-approaches","kind":"technology","name":"Synthetic lethality approaches","aka":[],"tldr":"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.","status":"approved","asOf":"2026-09-04","wikipedia":"https://en.wikipedia.org/wiki/Synthetic_lethality","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Synthetic_lethality"}],"tags":[],"related":[],"cancers":[],"sections":["targeted-therapy","drug-discovery"],"technologies":[],"targets":["parp","brca","atr","wee1","tp53"],"drugs":[],"companies":["amphista-therapeutics","foghorn-therapeutics","ideaya-biosciences","nimbus-therapeutics","plexium","repare-therapeutics","tango-therapeutics"],"institutions":[],"pathways":[],"terms":["synthetic-lethality"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"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"]},"route":"/technologies/synthetic-lethality-approaches/","neighbours":{"section":[{"id":"drug-discovery","kind":"section","name":"Drug Discovery Platforms","route":"/fronts/drug-discovery/"},{"id":"targeted-therapy","kind":"section","name":"Targeted Therapy","route":"/fronts/targeted-therapy/"}],"target":[{"id":"atr","kind":"target","name":"ATR","route":"/targets/atr/"},{"id":"brca","kind":"target","name":"BRCA1 / BRCA2 (HRD)","route":"/targets/brca/"},{"id":"parp","kind":"target","name":"PARP","route":"/targets/parp/"},{"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/"}],"company":[{"id":"amphista-therapeutics","kind":"company","name":"Amphista Therapeutics","route":"/companies/amphista-therapeutics/"},{"id":"debiopharm","kind":"company","name":"Debiopharm","route":"/companies/debiopharm/"},{"id":"foghorn-therapeutics","kind":"company","name":"Foghorn Therapeutics","route":"/companies/foghorn-therapeutics/"},{"id":"ideaya-biosciences","kind":"company","name":"IDEAYA Biosciences","route":"/companies/ideaya-biosciences/"},{"id":"nimbus-therapeutics","kind":"company","name":"Nimbus Therapeutics","route":"/companies/nimbus-therapeutics/"},{"id":"plexium","kind":"company","name":"Plexium","route":"/companies/plexium/"},{"id":"repare-therapeutics","kind":"company","name":"Repare Therapeutics","route":"/companies/repare-therapeutics/"},{"id":"tango-therapeutics","kind":"company","name":"Tango Therapeutics","route":"/companies/tango-therapeutics/"}],"term":[{"id":"synthetic-lethality","kind":"term","name":"Synthetic lethality","route":"/terms/synthetic-lethality/"}],"cancer":[{"id":"mesothelioma","kind":"cancer","name":"Mesothelioma","route":"/cancers/mesothelioma/"},{"id":"ovarian","kind":"cancer","name":"Ovarian cancer","route":"/cancers/ovarian/"}],"idea":[{"id":"idea-moon-synthetic-lethality-map-every-driver","kind":"idea","name":"A synthetic lethality map for every cancer driver in every tissue context","route":"/ideas/idea-moon-synthetic-lethality-map-every-driver/"},{"id":"idea-bio1-paralog-synthetic-lethality","kind":"idea","name":"Attack the backup copy when a tumour has lost the original gene","route":"/ideas/idea-bio1-paralog-synthetic-lethality/"},{"id":"idea-bio2-mechanism-defined-baskets","kind":"idea","name":"Group trials by broken mechanism, not by organ or single mutation","route":"/ideas/idea-bio2-mechanism-defined-baskets/"},{"id":"idea-bio1-persister-ferroptosis","kind":"idea","name":"Kill the sleeping survivor cells with iron-dependent cell 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genomics","route":"/technologies/crispr-screens/"},{"id":"high-throughput-screening-libraries","kind":"technology","name":"High-throughput screening and DNA-encoded libraries","route":"/technologies/high-throughput-screening-libraries/"},{"id":"metabolic-therapy","kind":"technology","name":"Metabolic therapy: starving the tumour of a nutrient","route":"/technologies/metabolic-therapy/"}],"institution":[{"id":"broad-institute","kind":"institution","name":"Broad Institute of MIT and Harvard","route":"/institutions/broad-institute/"},{"id":"newcastle-cancer-centre","kind":"institution","name":"Newcastle Cancer Centre / Northern Centre for Cancer Care","route":"/institutions/newcastle-cancer-centre/"}],"pathway":[{"id":"ddr","kind":"pathway","name":"DNA damage response & homologous recombination","route":"/pathways/ddr/"},{"id":"replication-stress","kind":"pathway","name":"DNA replication 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Map)","route":"/collections/depmap/"}],"person":[{"id":"alan-ashworth","kind":"person","name":"Alan Ashworth","route":"/people/alan-ashworth/"},{"id":"alan-dandrea","kind":"person","name":"Alan D. D'Andrea","route":"/people/alan-dandrea/"},{"id":"chris-lord","kind":"person","name":"Christopher Lord","route":"/people/chris-lord/"},{"id":"francisca-vazquez","kind":"person","name":"Francisca Vazquez","route":"/people/francisca-vazquez/"},{"id":"thomas-helleday","kind":"person","name":"Thomas Helleday","route":"/people/thomas-helleday/"}],"bottleneck":[{"id":"b-undruggable-targets","kind":"bottleneck","name":"The undruggable drivers","route":"/bottlenecks/b-undruggable-targets/"}],"paper":[{"id":"paper-depmap-tsherniak-cell-2017","kind":"paper","name":"Defining a Cancer Dependency Map: which genes each cancer cell line cannot live without","route":"/key-papers/paper-depmap-tsherniak-cell-2017/"},{"id":"paper-olympia-nejm-2021","kind":"paper","name":"OlympiA: a year of olaparib after surgery for BRCA-mutated, high-risk early breast cancer","route":"/key-papers/paper-olympia-nejm-2021/"},{"id":"paper-paola-1-nejm-2019","kind":"paper","name":"PAOLA-1: olaparib added to bevacizumab maintenance in newly diagnosed ovarian cancer, with benefit confined to HRD-positive tumours","route":"/key-papers/paper-paola-1-nejm-2019/"},{"id":"paper-solo-1-nejm-2018","kind":"paper","name":"SOLO-1: two years of olaparib maintenance after first-line chemotherapy for BRCA-mutated ovarian cancer","route":"/key-papers/paper-solo-1-nejm-2018/"}],"roadmap":[{"id":"drug-discovery-roadmap","kind":"roadmap","name":"Drug discovery roadmap: screening in mice → maps of dependency → designing in silico","route":"/roadmaps/drug-discovery-roadmap/"},{"id":"targeted-therapy-roadmap","kind":"roadmap","name":"Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall","route":"/roadmaps/targeted-therapy-roadmap/"}]}}