{"entity":{"id":"idea-moon-synthetic-lethality-map-every-driver","kind":"idea","name":"A synthetic lethality map for every cancer driver in every tissue context","aka":[],"tldr":"For each cancer-causing mutation, find every gene the cancer cell newly depends on, in every tissue, so that even undruggable drivers get druggable partners.","summary":"PARP inhibitors in BRCA-mutant cancers proved synthetic lethality can be turned into medicine; DepMap has screened around two thousand cell lines but coverage of driver-context combinations, in vivo dependencies and combination interactions is incomplete. The proposal is a systematic programme: isogenic and patient-derived models for each of the roughly 100 recurrent drivers across major tissue contexts, genome-wide CRISPR knockout, activation and base-editing screens in vitro and in vivo (including immune-competent settings), and drug-combination anchor screens, released openly with a standardised dependency confidence score.","asOf":"2026-09-08","links":[{"label":"DepMap","url":"https://depmap.org/portal/"}],"tags":[],"related":[],"cancers":[],"sections":[],"technologies":["crispr-screens","synthetic-lethality-approaches","organoids","pdx-models"],"targets":["tp53","kras","parp"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["synthetic-lethality"],"trials":[],"people":[],"bottlenecks":["b-undruggable-targets","b-resistance"],"keyPapers":["paper-vogelstein-surfing-p53-network-nature-2000"],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"The map yields at least twenty validated context-specific dependencies for drivers currently considered undruggable (MYC, mutant TP53 loss, SMARCA4, ARID1A) that translate into clinical programmes within a decade.","rationale":"Dependencies are context-dependent and rarely visible in a single model; systematic coverage is what made the BRCA-PARP relationship exploitable, and screening cost has fallen by orders of magnitude.","test":"Fund the first 20 driver-context pairs; success is prospective validation of at least three new dependencies in patient-derived models with drug-like inhibitors.","maturity":"preclinical-evidence","actor":"research","cost":"large","horizonYears":5},"route":"/ideas/idea-moon-synthetic-lethality-map-every-driver/","neighbours":{"technology":[{"id":"crispr-screens","kind":"technology","name":"CRISPR functional genomics","route":"/technologies/crispr-screens/"},{"id":"organoids","kind":"technology","name":"Patient-derived organoids","route":"/technologies/organoids/"},{"id":"pdx-models","kind":"technology","name":"Patient-derived xenografts","route":"/technologies/pdx-models/"},{"id":"synthetic-lethality-approaches","kind":"technology","name":"Synthetic lethality approaches","route":"/technologies/synthetic-lethality-approaches/"}],"target":[{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"},{"id":"parp","kind":"target","name":"PARP","route":"/targets/parp/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"term":[{"id":"synthetic-lethality","kind":"term","name":"Synthetic lethality","route":"/terms/synthetic-lethality/"}],"bottleneck":[{"id":"b-resistance","kind":"bottleneck","name":"Acquired resistance to every therapy","route":"/bottlenecks/b-resistance/"},{"id":"b-undruggable-targets","kind":"bottleneck","name":"The undruggable drivers","route":"/bottlenecks/b-undruggable-targets/"}],"paper":[{"id":"paper-vogelstein-surfing-p53-network-nature-2000","kind":"paper","name":"Vogelstein, Lane and Levine 2000: surfing the p53 network","route":"/key-papers/paper-vogelstein-surfing-p53-network-nature-2000/"}]}}