title: Increased in vitro and in vivo sensitivity of BRCA2-associated pancreatic cancer to the poly(ADP-ribose) polymerase-1/2 inhibitor BMN 673.
abstract: BRCA2-associated pancreatic ductal adenocarcinoma (PDAC) may be sensitive to agents that target homology-directed DNA repair, such as DNA crosslinking agents (DCLs) and PARP inhibitors (PARPis). Here, we assessed the sensitivities of BRCA2-deficient (Capan-1) and BRCA2-proficient (MIA PaCa-2) PDAC cell lines to a panel of DCLs and PARPis. Compared to MIA PaCa-2, Capan-1 was significantly more sensitive to all tested DCLs and PARPis, with similar increased sensitivities to cisplatin and the PARPi BMN 673 compared to other DCLs and the PARPi veliparib. We provide further support for this observation by showing that shRNA-mediated BRCA2 knockdown in PANC-1, a BRCA2-proficient cell line, induces sensitization to cisplatin and BMN 673 but not to veliparib. These findings were validated in a PDAC murine xenograft model derived from a patient with bi-allelic BRCA2 mutations. We found 64% and 61% tumor growth inhibition of this xenograft with cisplatin and BMN 673 treatments, respectively. Cisplatin and BMN 673 treatments reduced cellular proliferation and induced apoptosis. Our findings support a personalized treatment approach for BRCA2-associated PDAC.
authors: Rosalind and Morris Goodman Cancer Research Centre, McGill University, 1160 Pine Ave. West, Montreal, Quebec, Canada H3A 1A3; The Research Institute of the McGill University Health Centre, 1001 Decarie Boulevard, Montreal, Quebec, Canada H4A 3J1.
authors: Alexandra-Zoe
authors: AZ
authors: Andrei
authors: Rosalind and Morris Goodman Cancer Research Centre, McGill University, 1160 Pine Ave. West, Montreal, Quebec, Canada H3A 1A3; The Research Institute of the McGill University Health Centre, 1001 Decarie Boulevard, Montreal, Quebec, Canada H4A 3J1.
authors: Anita
authors: A
authors: Hall
authors: Rosalind and Morris Goodman Cancer Research Centre, McGill University, 1160 Pine Ave. West, Montreal, Quebec, Canada H3A 1A3; The Research Institute of the McGill University Health Centre, 1001 Decarie Boulevard, Montreal, Quebec, Canada H4A 3J1.
authors: Alyssa L
authors: AL
authors: Smith
authors: Rosalind and Morris Goodman Cancer Research Centre, McGill University, 1160 Pine Ave. West, Montreal, Quebec, Canada H3A 1A3; The Research Institute of the McGill University Health Centre, 1001 Decarie Boulevard, Montreal, Quebec, Canada H4A 3J1.
authors: Claire
authors: C
authors: Bascuñana
authors: Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec, Canada H3G 1Y6.
authors: Abba
authors: A
authors: Malina
authors: The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario, Canada M5G 1X5.
authors: Ashton
authors: A
authors: Connor
authors: Department of Pathology, McGill University Health Centre, 1001 Decarie Boulevard, Montreal, Quebec, Canada H4A 3J1.
authors: Gulbeyaz
authors: G
authors: Altinel-Omeroglu
authors: Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec, Canada H3G 1Y6.
authors: Sidong
authors: S
authors: Huang
authors: Rosalind and Morris Goodman Cancer Research Centre, McGill University, 1160 Pine Ave. West, Montreal, Quebec, Canada H3A 1A3; Department of Biochemistry, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec, Canada H3G 1Y6.
authors: Jerry
authors: J
authors: Pelletier
authors: Centre for the Translational and Applied Genomics, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia, Canada V5Z 1L4.
authors: David
authors: D
authors: Huntsman
authors: The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario, Canada M5G 1X5.
authors: Steven
authors: S
authors: Gallinger
authors: Department of Pathology, McGill University Health Centre, 1001 Decarie Boulevard, Montreal, Quebec, Canada H4A 3J1.
authors: Atilla
authors: A
authors: Omeroglu
authors: The Research Institute of the McGill University Health Centre, 1001 Decarie Boulevard, Montreal, Quebec, Canada H4A 3J1.
authors: Peter
authors: P
authors: Metrakos
authors: Rosalind and Morris Goodman Cancer Research Centre, McGill University, 1160 Pine Ave. West, Montreal, Quebec, Canada H3A 1A3; The Research Institute of the McGill University Health Centre, 1001 Decarie Boulevard, Montreal, Quebec, Canada H4A 3J1. Electronic address: george.zogopoulos@mcgill.ca.
authors: George
authors: G
authors: Zogopoulos
mesh_terms: D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use; D055785:Gene Knockdown Techniques; D024522:Genes, BRCA2; D018095:Germ-Line Mutation; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics; D010793:Phthalazines / Q000627:therapeutic use*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors
chemical_list: D010793:Phthalazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C586365:talazoparib; D002945:Cisplatin
keywords: BMN 673; BRCA2; DNA repair; Pancreatic ductal adenocarcinoma; Personalized medicine