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When PARP inhibitors stop working in prostate cancer, the tumour has repaired the broken gene, and a blood test shows it has done so in several different ways at once.
About 20% of metastatic prostate cancers carry mutations in genes required for DNA repair by homologous recombination, such as BRCA2, and those defects confer synthetic lethality to PARP inhibitors. In ovarian and breast cancer, olaparib resistance has been associated with restoration of homologous recombination, including by BRCA2 mutation reversion. This study identified BRCA2 reversion mutations associated with olaparib and talazoparib resistance in patients with prostate cancer. Analysis of circulating cell-free DNA revealed reversion mutation heterogeneity that was not discernible from a single solid-tumour biopsy, and suggested that cell-free DNA can be used to monitor for the emergence of PARP inhibitor resistance.
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.
Shares Cancer Discovery, Cell-free DNA (cfDNA), Double-strand break repair: HR versus end joining, Resistance routes: how a blocked pathway comes back.
Shares Homologous recombination repair gene mutation in prostate cancer, Cell-free DNA (cfDNA), Double-strand break repair: HR versus end joining, BRCA1 / BRCA2 (HRD).
Shares Base excision repair, PARP & alkylation damage, Tumour (somatic or germline) BRCA1/2 mutation and HRR gene alterations, Homologous recombination repair gene mutation in prostate cancer, Synthetic lethality: paired dependencies.
Shares Tumour (somatic or germline) BRCA1/2 mutation and HRR gene alterations, Cell-free DNA (cfDNA), Double-strand break repair: HR versus end joining, Resistance routes: how a blocked pathway comes back.
Shares Base excision repair, PARP & alkylation damage, Synthetic lethality: paired dependencies, Double-strand break repair: HR versus end joining, Homologous recombination deficiency (HRD).
Shares Tumour (somatic or germline) BRCA1/2 mutation and HRR gene alterations, Homologous recombination repair gene mutation in prostate cancer, Cell-free DNA (cfDNA), Double-strand break repair: HR versus end joining.
Shares BRCA reversion mutations, Base excision repair, PARP & alkylation damage, Tumour (somatic or germline) BRCA1/2 mutation and HRR gene alterations, Homologous recombination repair gene mutation in prostate cancer.
Shares Base excision repair, PARP & alkylation damage, Synthetic lethality: paired dependencies, Double-strand break repair: HR versus end joining.