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Two genes are synthetically lethal when losing either alone is fine but losing both kills the cell. Cancers that have already lost one (a tumour suppressor you cannot put back) become uniquely dependent on the other, which you can drug. BRCA and PARP was the first proof; a dozen more pairs are now in trials.
Genome-wide CRISPR screens (DepMap, Project Score) and clinical experience have mapped paired dependencies: BRCA1/2 or HRD → PARP1 and POLQ; ATM loss → ATR; TP53 loss or CCNE1 amplification → WEE1 and PKMYT1; MSI-H → WRN helicase; MTAP deletion (co-deleted with CDKN2A in ~15% of cancers) → PRMT5 and MAT2A (MTA-cooperative PRMT5 inhibitors AMG 193, MRTX1719); SMARCA4 loss → SMARCA2 (degraders); ARID1A loss → EZH2 and ATR; RB1 loss → Aurora kinase; VHL loss → HIF-2α (belzutifan is an oncogene-addiction-style version); KRAS mutation → SHP2, SOS1 (collateral dependencies). The concept also covers 'collateral lethality' (passenger deletions removing a paralogue) and 'induced essentiality' under therapy. Clinical success requires a clean biomarker, a selective inhibitor with a therapeutic window (PARP2 and marrow; PRMT5 in normal cells), and tolerance for resistance via restoration of the lost pathway (BRCA reversion) or loss of the dependency (53BP1).
A building held up by two pillars. Knock one out and it still stands; nobody notices. But a tumour has already lost one pillar to get where it is, so the second pillar, harmless to attack in every normal cell, brings the whole tumour down when it goes.
Germline and tumour testing for homologous recombination repair genes is now standard in metastatic prostate cancer, and olaparib is approved for BRCA-mutated disease after a hormonal agent.
The trial behind the second PARP inhibitor licensed in prostate cancer, and the evidence that a somatic BRCA alteration predicts response as well as an inherited one. Together with TOPARP-A it is why tumour as well as germline sequencing is recommended in metastatic disease.
It establishes that PARP inhibitor resistance in prostate cancer is a restored repair pathway rather than a bypass, which is why platinum and PARP inhibitors lose activity together, and it is the argument for sampling plasma rather than one lesion at progression.
Three pathway pages on OnCo cite this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing pages listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand.
MYC amplification, present in a fifth to a third of TNBC, is undruggable directly; this is the synthetic-lethal logic behind CDK (especially CDK9 and CDK1/2) inhibitor trials in the disease.
Shares PARP inhibitors: Synthetic lethality in the clinic, Analysis of circulating cell-free DNA identifies multiclonal heterogeneity of BRCA2 reversion mutations associated with resistance to PARP inhibitors, PROfound: olaparib for metastatic castration-resistant prostate cancer with homologous recombination repair gene alterations, TRITON2: rucaparib in men with metastatic castration-resistant prostate cancer harbouring a BRCA1 or BRCA2 alteration and the tags mechanism, mechanics-atlas.
Shares PRMT5 (MTAP-deleted cancers), Synthetic lethality, Oncogene addiction, Synthetic lethality approaches and the tags mechanism, mechanics-atlas.
Shares HRD & BRCA testing, DNA damage response & homologous recombination, Double-strand break repair: HR versus end joining, Mismatch repair & microsatellite instability and the tags mechanism, mechanics-atlas.
Shares MYC pathway activation in triple-negative breast cancer is synthetic lethal with CDK inhibition, WEE1, DNA replication stress, TP53 and the tags mechanism, mechanics-atlas.
Shares ATR, DNA replication stress, DNA damage response & homologous recombination and the tags mechanism, mechanics-atlas.
Shares VHL / HIF oxygen sensing, HIF-2α, The p53 network (guardian of the genome), Prostate cancer and the tags mechanism, mechanics-atlas.
Shares VHL / HIF oxygen sensing, HIF-2α, Belzutifan and the tags mechanism, mechanics-atlas.
Shares VHL / HIF oxygen sensing, HIF-2α and the tags mechanism, mechanics-atlas.