# A synthetic lethality map for every cancer driver in every tissue context

Source: https://onco.cc/ideas/idea-moon-synthetic-lethality-map-every-driver/  
OnCo record `idea-moon-synthetic-lethality-map-every-driver` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Fields

- Kind: Idea
- Last checked: 2026-09-08
- 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.
- Proposed 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

## Sources

- DepMap: https://depmap.org/portal/

## Connected records

- technologies: [CRISPR functional genomics](https://onco.cc/technologies/crispr-screens/), [Patient-derived organoids](https://onco.cc/technologies/organoids/), [Patient-derived xenografts](https://onco.cc/technologies/pdx-models/), [Synthetic lethality approaches](https://onco.cc/technologies/synthetic-lethality-approaches/)
- targets: [KRAS](https://onco.cc/targets/kras/), [PARP](https://onco.cc/targets/parp/), [TP53](https://onco.cc/targets/tp53/)
- terms: [Synthetic lethality](https://onco.cc/terms/synthetic-lethality/)
- bottlenecks: [Acquired resistance to every therapy](https://onco.cc/bottlenecks/b-resistance/), [The undruggable drivers](https://onco.cc/bottlenecks/b-undruggable-targets/)
- key papers: [Vogelstein, Lane and Levine 2000: surfing the p53 network](https://onco.cc/key-papers/paper-vogelstein-surfing-p53-network-nature-2000/)

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