{"entity":{"id":"idea-bio1-paralog-synthetic-lethality","kind":"idea","name":"Attack the backup copy when a tumour has lost the original gene","aka":[],"tldr":"Tumours often lose one of a pair of near-identical genes. They then depend entirely on the remaining copy, which a drug can block, killing only the cancer.","summary":"SMARCA4-mutant cancers depend on SMARCA2; MTAP-deleted cancers depend on PRMT5 in a methylthioadenosine-dependent manner; other paralog pairs (for example ARID1A/ARID1B, ENO1/ENO2) show the same logic. Paralog dependencies are the most systematic way to exploit tumour-suppressor loss, which is otherwise undruggable. Selective SMARCA2 degraders and MTA-cooperative PRMT5 inhibitors have reached the clinic.","asOf":"2026-09-08","links":[{"label":"Bottleneck evidence (The undruggable drivers): Dang et al., Drugging the 'undruggable' cancer targets (Nature Reviews Cancer 2017)","url":"https://doi.org/10.1038/nrc.2017.36"}],"tags":[],"related":["idea-mtap-prmt5-mesothelioma"],"cancers":[],"sections":[],"technologies":["crispr-screens","synthetic-lethality-approaches","protac-degrader"],"targets":[],"drugs":[],"companies":[],"institutions":["broad-institute","icr-london"],"pathways":[],"terms":["synthetic-lethality"],"trials":[],"people":[],"bottlenecks":["b-undruggable-targets"],"keyPapers":["paper-dang-nat-rev-cancer"],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"A genome-wide paralog dependency map across 500 cell lines yields at least ten new pairs where loss-of-function in the tumour creates a greater than five-fold selective dependency confirmed in vivo.","rationale":"Tumour suppressor loss is more common than oncogene activation but has almost no direct therapies; paralog buffering converts loss into a positive drug target, exactly as PARP inhibition did for BRCA loss.","test":"Dual-guide CRISPR paralog screens in a large line panel with matched genotype annotation; validate the top hits in isogenic pairs and PDX models before chemistry investment.","maturity":"early-clinical","actor":"research","cost":"medium","horizonYears":5},"route":"/ideas/idea-bio1-paralog-synthetic-lethality/","neighbours":{"idea":[{"id":"idea-mtap-prmt5-mesothelioma","kind":"idea","name":"PRMT5/MAT2A synthetic lethality for MTAP-deleted mesothelioma","route":"/ideas/idea-mtap-prmt5-mesothelioma/"}],"technology":[{"id":"crispr-screens","kind":"technology","name":"CRISPR functional genomics","route":"/technologies/crispr-screens/"},{"id":"protac-degrader","kind":"technology","name":"PROTACs & molecular glues (targeted protein degradation)","route":"/technologies/protac-degrader/"},{"id":"synthetic-lethality-approaches","kind":"technology","name":"Synthetic lethality approaches","route":"/technologies/synthetic-lethality-approaches/"}],"institution":[{"id":"broad-institute","kind":"institution","name":"Broad Institute of MIT and Harvard","route":"/institutions/broad-institute/"},{"id":"icr-london","kind":"institution","name":"The Institute of Cancer Research","route":"/institutions/icr-london/"}],"term":[{"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-dang-nat-rev-cancer","kind":"paper","name":"Drugging the 'undruggable' cancer targets","route":"/key-papers/paper-dang-nat-rev-cancer/"}]}}