@article{f0568c8894964be2a4f5541eeb0b4a1b,
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.",
keywords = "BMN 673, BRCA2, DNA repair, Pancreatic ductal adenocarcinoma, Personalized medicine",
author = "Andrei, {Alexandra Zoe} and Anita Hall and Smith, {Alyssa L.} and Claire Bascu{\~n}ana and Abba Malina and Ashton Connor and Gulbeyaz Altinel-Omeroglu and Sidong Huang and Jerry Pelletier and David Huntsman and Steven Gallinger and Atilla Omeroglu and Peter Metrakos and George Zogopoulos",
note = "Funding Information: This article is dedicated to the late Rosalind Goodman for her philanthropy and tireless efforts to promote cancer research in our institution and community. We would like to thank Dr. Michel Tremblay for his guidance with the xCELLigence assays, Dr. Dongmei Zuo and the Histology Core at the Goodman Cancer Research Centre for technical support with the immunohistochemistry, and Dr. William Foulkes for facilitating rapid clinical genetic testing and confirmation of the germline mutation in our patient. AZA is a Canderel Research Fellowship recipient. GZ is a clinical research scholar of the Fonds de recherche du Qu{\'e}bec – Sant{\'e}. This work was supported by funding from the Canadian Institutes of Health Research (to DH, GZ MOP-123517 ; to JP MOP-106530 ), the Canadian Cancer Society Research Institute (to SG, GZ 702316 ; to JP 702778 ) and the Research Institute of the McGill University Health Centre (to GZ). Publisher Copyright: {\textcopyright} 2015 Elsevier Ireland Ltd.",
year = "2015",
month = aug,
day = "1",
doi = "10.1016/j.canlet.2015.04.003",
language = "English (US)",
volume = "364",
pages = "8--16",
journal = "Cancer Letters",
issn = "0304-3835",
publisher = "Elsevier Ireland Ltd",
number = "1",
}