A synthetic lethality map for every cancer driver in every tissue context
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.
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.
- The undruggable drivers · The proteins that drive most cancers, such as MYC, mutant p53 and most RAS variants, still have no good drug.
- Acquired resistance to every therapy · Nearly every targeted therapy stops working within months to a few years as the tumour adapts.
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- InstitutionCentro Nacional de Investigaciones Oncológicas (CNIO)
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- PersonChristopher Lord
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