Synthetic lethality
Two genes where losing either alone is fine but losing both kills the cell. Cancers that have lost one become vulnerable to drugs against the other.
BRCA/PARP is the proven pair. Others in development: MTAP/PRMT5, MSI/WRN, HRD/POLQ, TP53/WEE1, SMARCA4/SMARCA2, ARID1A/EZH2. Mapped systematically by CRISPR screens.
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.
Pages like this
not linked directly; found by shared links- TargetPARP
Shares Christopher Lord, A synthetic lethality map for every cancer driver in every tissue context, Newcastle Cancer Centre / Northern Centre for Cancer Care, Tumour suppressor gene.
- TargetATR
Shares Base excision repair, PARP & alkylation damage, DNA replication stress, Synthetic lethality: paired dependencies, Double-strand break repair: HR versus end joining.
- PathwayDNA damage response & homologous recombination
Shares Base excision repair, PARP & alkylation damage, DNA replication stress, Synthetic lethality: paired dependencies, Double-strand break repair: HR versus end joining.
- TargetBRCA1 / BRCA2 (HRD)
Shares Christopher Lord, Newcastle Cancer Centre / Northern Centre for Cancer Care, Tumour suppressor gene, SOLO-1: two years of olaparib maintenance after first-line chemotherapy for BRCA-mutated ovarian cancer.
- TargetWEE1
Shares DNA replication stress, Synthetic lethality: paired dependencies, Double-strand break repair: HR versus end joining, Synthetic lethality approaches.
- ProductOlaparib
Shares 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, Base excision repair, PARP & alkylation damage, OlympiA: a year of olaparib after surgery for BRCA-mutated, high-risk early breast cancer.
- ProductNiraparib
Shares Base excision repair, PARP & alkylation damage, Synthetic lethality: paired dependencies, Double-strand break repair: HR versus end joining, PARP inhibitors.
- TermHomologous recombination deficiency (HRD)
Shares 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, Base excision repair, PARP & alkylation damage, Synthetic lethality: paired dependencies.