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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.
Shares Synthetic lethality, Synthetic lethality approaches, CRISPR functional genomics, The undruggable drivers.
Shares Synthetic lethality, Synthetic lethality approaches, CRISPR functional genomics, The undruggable drivers.
Shares Synthetic lethality, Synthetic lethality approaches, CRISPR functional genomics, The undruggable drivers.
Shares Synthetic lethality approaches, CRISPR functional genomics, Patient-derived organoids.
Shares Patient-derived xenografts, CRISPR functional genomics, Patient-derived organoids.
Shares Vogelstein, Lane and Levine 2000: surfing the p53 network, The undruggable drivers, TP53.
Shares Synthetic lethality, Synthetic lethality approaches, CRISPR functional genomics.
Shares Vogelstein, Lane and Levine 2000: surfing the p53 network, The undruggable drivers, TP53, KRAS.