title: Secondary mutations in BRCA2 associated with clinical resistance to a PARP inhibitor.
abstract: PARP inhibitors (PARPi) for the treatment of BRCA1 or BRCA2 deficient tumours are currently the focus of seminal clinical trials exploiting the concept of synthetic lethality. Although clinical resistance to PARPi has been described, the mechanism underlying this has not been elucidated. Here, we investigate tumour material from patients who had developed resistance to the PARPi olaparib, subsequent to showing an initial clinical response. Massively parallel DNA sequencing of treatment-naive and post-olaparib treatment biopsies identified tumour-specific BRCA2 secondary mutations in olaparib-resistant metastases. These secondary mutations restored full-length BRCA2 protein, and most likely cause olaparib resistance by re-establishing BRCA2 function in the tumour cells.
authors.affiliation: Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.
authors.forename: Louise J
authors.initials: LJ
authors.lastname: Barber
authors.forename: Shahneen
authors.initials: S
authors.lastname: Sandhu
authors.forename: Lina
authors.initials: L
authors.lastname: Chen
authors.forename: James
authors.initials: J
authors.lastname: Campbell
authors.forename: Iwanka
authors.initials: I
authors.lastname: Kozarewa
authors.forename: Kerry
authors.initials: K
authors.lastname: Fenwick
authors.forename: Ioannis
authors.initials: I
authors.lastname: Assiotis
authors.forename: Daniel Nava
authors.initials: DN
authors.lastname: Rodrigues
authors.forename: Jorge S
authors.initials: JS
authors.lastname: Reis Filho
authors.forename: Victor
authors.initials: V
authors.lastname: Moreno
authors.forename: Joaquin
authors.initials: J
authors.lastname: Mateo
authors.forename: L Rhoda
authors.initials: LR
authors.lastname: Molife
authors.forename: Johann
authors.initials: J
authors.lastname: De Bono
authors.forename: Stan
authors.initials: S
authors.lastname: Kaye
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lord
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000556:secondary; D000970:Antineoplastic Agents / Q000494:pharmacology*; D024682:BRCA2 Protein / Q000235:genetics*; D018567:Breast Neoplasms, Male / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D003131:Combined Modality Therapy; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D010793:Phthalazines / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D017422:Sequence Analysis, DNA
chemical_list: D000970:Antineoplastic Agents; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C531550:olaparib