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Finding a second gene that a cancer needs only because its first gene is broken, then hitting the second one.
PARP inhibition in BRCA loss is the proven case. Next: PRMT5 inhibitors (MTAP-deleted tumours, ~15% of cancers; AMG 193, MRTX1719 in phase 2/3), WRN inhibitors (MSI-high), POLQ inhibitors (HRD), and WEE1/ATR in TP53-mutant and CCNE1-amplified tumours. CRISPR screens (DepMap) systematically map these dependencies.
Genetic interaction where loss of both genes, but neither alone, is lethal.
Everyone with HER2-negative early breast cancer that meets high-risk criteria should be offered germline BRCA testing, because a positive result now changes treatment: a year of olaparib after chemotherapy reduces relapse and death. It does not apply to low-risk tumours, HER2-positive disease, or somatic-only BRCA mutations.
Women with newly diagnosed advanced ovarian cancer should have their tumour tested for BRCA mutations and homologous recombination deficiency, because those who are HRD-positive gain years of additional disease control and better survival from adding olaparib to bevacizumab maintenance. Those who are HRD-negative gain nothing from olaparib in this combination and should not be exposed to its toxicity and cost. HRD testing has become a routine part of ovarian cancer care as a result.
Every woman diagnosed with advanced high-grade ovarian cancer should be tested for BRCA mutations at diagnosis, because those who carry one should receive two years of olaparib after chemotherapy, which greatly extends the time in remission and improves long-term survival. The plateau in the survival curves suggests some patients are cured by this approach. Toxicity is mostly anaemia, fatigue and nausea, and the two-year limit appears sufficient.
DepMap is the lookup table drug hunters use to ask: which cancers would die if we blocked this gene, and how would we recognise them? It generated targets such as WRN and PRMT5-MTAP now in clinical trials, and it is public.
Query for this technology: (TITLE:"synthetic lethality" OR ABSTRACT:"synthetic lethality" OR TITLE:"synthetic lethal" OR ABSTRACT:"synthetic lethal") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about Synthetic lethality approaches, not a curated reading list.
Shares ATR and CHK1 inhibitors, Christopher Lord, Thomas Helleday, Alan D. D'Andrea.
Shares ATR, DNA replication stress, Synthetic lethality, DNA damage response & homologous recombination.
Shares ATR, DNA replication stress, DNA damage response & homologous recombination, PARP.
Shares PAOLA-1: olaparib added to bevacizumab maintenance in newly diagnosed ovarian cancer, with benefit confined to HRD-positive tumours, Synthetic lethality: paired dependencies, DNA damage response & homologous recombination, Double-strand break repair: HR versus end joining.
Shares Synthetic lethality, Synthetic lethality: paired dependencies, DNA damage response & homologous recombination, Double-strand break repair: HR versus end joining.
Shares Drivers, passengers & the two-hit model, DNA damage response & homologous recombination, Double-strand break repair: HR versus end joining, Mismatch repair & microsatellite instability.
Shares Synthetic lethality, Synthetic lethality: paired dependencies, Double-strand break repair: HR versus end joining, PARP.
Shares Thomas Helleday, Alan Ashworth, SOLO-1: two years of olaparib maintenance after first-line chemotherapy for BRCA-mutated ovarian cancer, PAOLA-1: olaparib added to bevacizumab maintenance in newly diagnosed ovarian cancer, with benefit confined to HRD-positive tumours.
Open-source projects that implement or serve this technology, from OnCo's own catalogue: licence and last activity as the repository reported them on the day of the fetch. Listing is not endorsement; check the licence before reuse and the validation before clinical use.
The code behind the Cancer Dependency Map portal, where CRISPR screens and drug sensitivities across cancer cell lines are explored openly.
Open-source software, hardware and data projects catalogued by a third party, the Open Medical Registry, that bear on this technology. Listing is not endorsement; check each project's own licence and validation before clinical use.
Synthetic lethality (SL) is a promising gold mine for the discovery of anti-cancer drug targets.
From the Open Medical Registry (openmedical.sh), an MIT-licensed catalogue of open-source medicine. Blurbs are one line from each registry record; every project keeps its own licence.