Increased in vitro and in vivo sensitivity of BRCA2-associated pancreatic cancer to the poly(ADP-ribose) polymerase-1/2 inhibitor BMN 673. Issue 1 (1st August 2015)

• Record Type: Journal Article
• Authors: Andrei, Alexandra-Zoe; Hall, Anita; Smith, Alyssa L.; Bascuñana, Claire; Malina, Abba; Connor, Ashton; Altinel-Omeroglu, Gulbeyaz; Huang, Sidong; Pelletier, Jerry; Huntsman, David; Gallinger, Steven; Omeroglu, Atilla; Metrakos, Peter; Zogopoulos, George
• Is Part Of: Cancer letters. Volume 364:Issue 1(2015)
• Page Start: 8
• Page End: 16
• Publication Date: 2015-08-01
• Subjects: Pancreatic ductal adenocarcinoma -- BRCA2 -- DNA repair -- BMN 673 -- Personalized medicine; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2015.04.003
• Languages: English
• ISSNs: 0304-3835

Abstract

Highlights: BRCA2 -associated PDAC is sensitive to agents exploiting DNA repair defects. BRCA2-deficient PDAC cells are sensitive to cisplatin and BMN 673. BMN 673 inhibits tumor growth by 61% in a BRCA2 PDAC xenograft model. 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.