Abstract 3074: Selective lethality of cisplatin in pancreatic cancer is dependent on mitotic functions of BRCA2

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDA) is an aggressive malignancy with a 5-year survival rate of just 8%. Mutations in BRCA2 are among the most common known germline alterations that predispose to PDA. While the sensitivity of BRCA2-mutant breast and ovarian tumors to platinum compounds has long been recognized, the recent approval a PARP inhibitor in BRCA2-mutant ovarian cancer confers hope that such tumors might be targeted with greatly reduced toxicity. To test whether PDA exhibits a similar genetic susceptibility to these agents, we carried out preclinical intervention studies in Kras/p53-mutant genetically engineered mouse models (KPC mice) with or without the additional mutation of BRCA2 (KPCB2 mice). Mice were enrolled based on 3D ultrasound imaging criteria to assure similar initial tumor burden, and tumor growth was monitored longitudinally by ultrasound. To our surprise, loss of Brca2 failed to sensitize pancreatic tumors to Parp inhibition and did not provide additional benefit in combination with cisplatin treatment. By contrast, cisplatin induced substantial regressions in most KPCB2 tumors, leading to a >3-fold increase in overall survival, while having no effect on the growth or survival of mice with wild-type BRCA2. More surprisingly, the efficacy of cisplatin was not shared with oxaliplatin, even at higher doses. While BRCA2 is primarily known for its role in homology-directed repair, a network biology analysis of the function of BRCA2 in human pancreatic cancer led us to investigate the role of BRCA2 in mitosis. Wild type BRCA2 protein localizes to the midbody- a structure formed during the final stages of telophase- and plays and poorly understood role in the final abscission of cytoplasm between two dividing cells. Timelapse video microscopy of KPCB2 tumor cells treated once weekly for 2 hours with cisplatin revealed the frequent induction of endoreduplication and eventual formation of polyploid giant cells subsequent death. Similar cells were found throughout KPCB2 tumors during regression in response to cisplatin treatment, but were largely absent from tumors in other treatment arms. Mechanism studies found that BRCA2 deficient PDA cells are susceptible to replicative stress following cisplatin treatment that selectively leads to the formation of radial chromosomes that cannot be resolved during mitosis. These studies argue for the consideration of cisplatin-based (rather than oxaliplatin-based) regimens for the treatment of BRCA2-mutant pancreatic tumors. Citation Format: Barbara Orelli, Hans C. Maurer, Carmine Palermo, Steven A. Sastra, Kenneth P. Olive. Selective lethality of cisplatin in pancreatic cancer is dependent on mitotic functions of BRCA2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3074. doi:10.1158/1538-7445.AM2017-3074