What is Synthetic Lethality?

A principle from genetics that lets us kill cancer cells while sparing healthy ones — and the reason PrecisionSL exists.

Synthetic lethality: a normal cell with wild-type Gene A and B remains viable when Gene B is inhibited; a cancer cell with mutated Gene A dies when Gene B is also inhibited.
Created with BioRender.com

The principle

Synthetic lethality occurs when the simultaneous loss of two genes kills a cell, but the loss of either one alone does not.

In a healthy cell with both genes intact, inhibiting one is tolerated — the other gene compensates. In a cancer cell where one of the two is already mutated, inhibiting the second one is lethal: there is no compensation left.

Because the lethality only triggers in cells that already carry the cancer-driving mutation, synthetic lethal drugs can selectively kill tumour cells while leaving healthy tissue intact.

Why it matters for cancer treatment

Many of the most common cancer drivers are tumour suppressor genes that have lost function — for example TP53, BRCA1, BRCA2, RB1, PTEN. Restoring a lost protein directly is extraordinarily hard, which is why these mutations have historically been considered “undruggable.”

Synthetic lethality reframes the problem. Instead of trying to fix the broken gene, we look for a partner gene whose inhibition would be lethal only in the context of the broken one — and target the partner with a drug.

The clinical archetype is BRCA1/BRCA2-mutant cancers treated with PARP inhibitors like olaparib. BRCA1/2 cells already have impaired DNA repair; PARP inhibition pushes them past the breaking point while sparing BRCA-intact normal cells.

How PrecisionSL uses it

For each gene in our database, PrecisionSL surfaces:

  • The gene’s mutation profile across seven cancer subtypes (from COSMIC).
  • If the gene is an oncogene, drugs that target it directly.
  • If the gene is a tumour suppressor, drugs that target its synthetic lethal partners — combining four SSL datasets (SynLethDB, BioGRID, SLOrth, MEXDRUGS) for partner discovery.
  • Approved drugs, repositionable drugs from cansar, and live clinical trials from ClinicalTrials.gov for each gene/cancer pair.

The result is a gene-first view of treatment options driven by the synthetic lethality model — useful for researchers exploring drug repurposing, clinicians looking for biomarker- matched trials, and students learning the field.

Ready to explore?

Search a gene