Resistance to therapy caused by intragenic deletion in BRCA2

• Published in: Nature 2008-02, Vol.451 (7182), p.1111-1115
• Main Authors: Ashworth, Alan, Edwards, Stacey L, Brough, Rachel, Lord, Christopher J, Natrajan, Rachael, Vatcheva, Radost, Levine, Douglas A, Boyd, Jeff, Reis-Filho, Jorge S
• Format: Article
• Language: English
• Subjects: Adenosine diphosphate; Aged; Alleles; Amino Acid Sequence; Antineoplastic agents; Base Sequence; Biological and medical sciences; BRCA2 Protein - deficiency; BRCA2 Protein - genetics; Breast cancer; Carboplatin - pharmacology; Cell Line, Tumor; Cellular biology; Chemotherapy; Chromosome Aberrations - chemically induced; Deoxyribonucleic acid; DNA; Drug resistance; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Female; Female genital diseases; Fluorobenzenes - pharmacology; Gene Expression Regulation, Neoplastic; Genes, BRCA2; Genomics; Gynecology. Andrology. Obstetrics; Humanities and Social Sciences; Humans; Inhibitor drugs; letter; Medical sciences; Middle Aged; Mitomycin - pharmacology; Molecular Sequence Data; multidisciplinary; Mutation; Mutation - genetics; Open Reading Frames - genetics; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology; Pharmacology. Drug treatments; Phthalazines - pharmacology; Poly(ADP-ribose) Polymerase Inhibitors; Recombination, Genetic - genetics; Science; Science (multidisciplinary); Sequence Deletion - genetics; Tumors
• ISSN: 0028-0836; 1476-4687; 1476-4679
• DOI: 10.1038/nature06548

Cells with loss of BRCA2 function are defective in homologous recombination (HR) and are highly sensitive to inhibitors of poly(ADP-ribose) polymerase (PARP), which provides the basis for a new therapeutic approach. Here we show that resistance to PARP inhibition can be acquired by deletion of a mutation in BRCA2. We derived PARP-inhibitor-resistant (PIR) clones from the human CAPAN1 pancreatic cancer cell line, which carries the protein-truncating c.6174delT frameshift mutation. PIR clones could form DNA-damage-induced RAD51 nuclear foci and were able to limit genotoxin-induced genomic instability, both hallmarks of a competent HR pathway. New BRCA2 isoforms were expressed in the resistant lines as a result of intragenic deletion of the c.6174delT mutation and restoration of the open reading frame (ORF). Reconstitution of BRCA2-deficient cells with these revertant BRCA2 alleles rescued PARP inhibitor sensitivity and HR deficiency. Most of the deletions in BRCA2 were associated with small tracts of homology, and possibly arose from error-prone repair caused by BRCA2 deficiency. Similar ORF-restoring mutations were present in carboplatin-resistant ovarian tumours from c.6174delT mutation carriers. These observations have implications for understanding drug resistance in BRCA mutation carriers as well as in defining functionally important domains within BRCA2.