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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.
Synthetic lethality describes two genes where losing either alone is tolerated but losing both kills the cell, so a cancer that has lost one becomes vulnerable to a drug against the other. BRCA and PARP is the proven pair; others in development include MTAP/PRMT5, MSI/WRN, HRD/POLQ, TP53/WEE1, SMARCA4/SMARCA2 and ARID1A/EZH2, and CRISPR screens map such pairs systematically. The concept links to the Synthetic lethality approaches, PARP inhibitors and CRISPR functional genomics technologies and is cited by the Ovarian cancer and Mesothelioma entries, The Institute of Cancer Research and Christopher Lord. Ideas drawing on it include PRMT5/MAT2A lethality for MTAP-deleted mesothelioma, a WRN inhibitor programme and a synthetic lethality map for every cancer driver.
Showing the technology this term belongs to: Synthetic lethality approaches.
The glossary entry explains the word; the readout page carries the scoring rule, the thresholds approvals use, the companion diagnostics and the tests.
The randomised proof for PARP inhibition in BRCA-altered prostate cancer, and the clearest evidence that the homologous recombination repair gene list should not be used as a single yes-or-no test. ATM-altered disease needs a different answer, and does not yet have one.
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.
It is the evidence that PALB2 and somatic BRCA2 belong in the PARP inhibitor conversation even though the olaparib label stops at germline BRCA.
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.
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.
Germline testing for every pancreatic cancer patient, platinum first line for BRCA carriers, and olaparib maintenance for those who respond are all downstream of POLO.
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.
Shares Phase II study of maintenance rucaparib in patients with platinum-sensitive advanced pancreatic cancer and a pathogenic germline or somatic variant in BRCA1, BRCA2, or PALB2, TRITON3: rucaparib or physician's choice in metastatic castration-resistant prostate cancer, TRITON2: rucaparib in men with metastatic castration-resistant prostate cancer harbouring a BRCA1 or BRCA2 alteration, Genome-wide loss of heterozygosity (gLOH).
Shares Christopher Lord, A synthetic lethality map for every cancer driver in every tissue context, Tumour suppressor gene, SOLO-1: two years of olaparib maintenance after first-line chemotherapy for BRCA-mutated ovarian cancer.
Shares TOPARP-A: DNA-repair defects and olaparib in metastatic prostate cancer, TRITON3: rucaparib or physician's choice in metastatic castration-resistant prostate cancer, TRITON2: rucaparib in men with metastatic castration-resistant prostate cancer harbouring a BRCA1 or BRCA2 alteration, Base excision repair, PARP & alkylation damage.
Shares POLO: maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer, Base excision repair, PARP & alkylation damage, DNA replication stress, Homologous recombination repair gene mutation in prostate cancer.
Shares TOPARP-A: DNA-repair defects and olaparib in metastatic prostate cancer, 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, TRITON3: rucaparib or physician's choice in metastatic castration-resistant prostate cancer.
Shares TOPARP-A: DNA-repair defects and olaparib in metastatic prostate cancer, TRITON3: rucaparib or physician's choice in metastatic castration-resistant prostate cancer, Genome-wide loss of heterozygosity (gLOH), Homologous recombination repair gene mutation in prostate cancer.
Shares DNA replication stress, Synthetic lethality: paired dependencies, Synthetic lethality approaches, Double-strand break repair: HR versus end joining.
Shares Base excision repair, PARP & alkylation damage, DNA replication stress, Synthetic lethality: paired dependencies, Synthetic lethality approaches.