# Attack the backup copy when a tumour has lost the original gene

Source: https://onco.cc/ideas/idea-bio1-paralog-synthetic-lethality/  
OnCo record `idea-bio1-paralog-synthetic-lethality` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Fields

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

## Sources

- Bottleneck evidence (The undruggable drivers): Dang et al., Drugging the 'undruggable' cancer targets (Nature Reviews Cancer 2017): https://doi.org/10.1038/nrc.2017.36

## Connected records

- ideas: [PRMT5/MAT2A synthetic lethality for MTAP-deleted mesothelioma](https://onco.cc/ideas/idea-mtap-prmt5-mesothelioma/)
- technologies: [CRISPR functional genomics](https://onco.cc/technologies/crispr-screens/), [PROTACs & molecular glues (targeted protein degradation)](https://onco.cc/technologies/protac-degrader/), [Synthetic lethality approaches](https://onco.cc/technologies/synthetic-lethality-approaches/)
- institutions: [Broad Institute of MIT and Harvard](https://onco.cc/institutions/broad-institute/), [The Institute of Cancer Research](https://onco.cc/institutions/icr-london/)
- terms: [Synthetic lethality](https://onco.cc/terms/synthetic-lethality/)
- bottlenecks: [The undruggable drivers](https://onco.cc/bottlenecks/b-undruggable-targets/)
- key papers: [Drugging the 'undruggable' cancer targets](https://onco.cc/key-papers/paper-dang-nat-rev-cancer/)

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