Synthetic lethality: paired dependencies
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).
In one picture
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.
Diagram
top- PARP inhibitors for BRCA/HRD (approved in four cancers)
- MTA-cooperative PRMT5 inhibitors for MTAP-deleted tumours (mesothelioma, NSCLC, pancreatic; phase 1-2)
- WEE1 (azenosertib), PKMYT1 (lunresertib) and ATR (ceralasertib, camonsertib) inhibitors in TP53-mutant, CCNE1-amplified and ATM-deficient tumours
- WRN inhibitors for MSI-H; SMARCA2 degraders for SMARCA4-deficient cancers
Pages like this
not linked directly; found by shared links- PathwayBase excision repair, PARP & alkylation damage
Shares ATR, Niraparib, Talazoparib, DNA replication stress and the tags mechanism, mechanics-atlas.
- PathwayMutagenesis & mutational signatures
Shares HRD & BRCA testing, Homologous recombination deficiency (HRD), DNA damage response & homologous recombination, Mismatch repair & microsatellite instability and the tags mechanism, mechanics-atlas.
- PathwayDrivers, passengers & the two-hit model
Shares PRMT5 (MTAP-deleted cancers), Synthetic lethality, Oncogene addiction, Synthetic lethality approaches and the tags mechanism, mechanics-atlas.
- PathwayThe cell-cycle engine (cyclins & CDKs)
Shares WEE1, DNA replication stress, TP53 and the tags mechanism, mechanics-atlas.
- PathwayDNA replication & origin licensing
Shares ATR, DNA replication stress, DNA damage response & homologous recombination and the tags mechanism, mechanics-atlas.
- PathwayThe angiogenic switch & tumour vessels
Shares Belzutifan, VHL / HIF oxygen sensing, HIF-2α and the tags mechanism, mechanics-atlas.
- PathwayUbiquitin–proteasome system & protein homeostasis
Shares VHL / HIF oxygen sensing, HIF-2α, The p53 network (guardian of the genome) and the tags mechanism, mechanics-atlas.
- PathwayThe pre-metastatic niche
Shares VHL / HIF oxygen sensing, HIF-2α and the tags mechanism, mechanics-atlas.