Abstract PR12: Selective lethality of cisplatin in pancreatic cancer is dependent on mitotic functions of BRCA2

Abstract

Abstract Pancreatic ductal adenocarcinoma is a highly aggressive malignancy that is broadly resistant to both cytotoxic and targeted therapeutic agents. However, patients with BRCA2 mutations are reported to have improved responsiveness to certain chemotherapies, and several trials are ongoing to determine their responsiveness to PARP inhibitors, which have shown efficacy in other types of BRCA-mutant cancers. The sensitivity of BRCA2-mutant tumors to platinum agents such as cisplatin is frequently ascribed to the loss of homology-directed repair (HDR) activity, a form of double-strand DNA break repair that requires BRCA2 function. In the absence of HDR, tumors are forced to rely on more error-prone repair mechanisms. Brca2 mutations are present in about 10% of human PDA cases, making it both the most prevalent hereditary alteration and the most frequent “actionable” mutation in pancreatic cancer. In order to study the role of BRCA2 in pancreatic cancer drug sensitivity, we carried out both short-term (10-day) and long-term (survival) intervention studies in three different models of PDA: KrasLSL.G12D/+; p53 LSL.R172H/+; PdxCretg/+ (KPC) mice, a well-validated preclinical model with intact brca2; KPC-Brca2+/-, which are germline heterozygous knockout for brca2; and KPC-Brca2F/F, in which both copies of Brca2 are deleted in the malignant pancreatic epithelial cells. Each model was treated with vehicle, cisplatin, niraparib (a Parp1 inhibitor), or cisplatin + niraparib. Analysis of post-treatment tumor samples in the short-term study compared to pretreatment biopsy samples demonstrated full inhibition of PARylation in response to niraparib treatment. As expected, the KPC mice proved fully resistant to all treatments, with no change in growth dynamics as measured by 3D high-resolution ultrasound. Surprisingly, Parp inhibition did not extend the overall survival of KPC-Brca2F/F mice, although a subset of individual tumors showed transient responses. By contrast, cisplatin monotherapy induced profound regressions in KPC-Brca2F/F pancreatic tumors, including one tumor with a complete response by ultrasound. Overall survival was greatly extended in the KPC-Brca2F/F mice and modestly improved in KPC-Brca2+/- mice (which do not undergo LOH). Notably, we found that the sensitivity of Brca-deficient pancreatic tumors was highly specific to certain drugs, and even varied widely between different platinum compounds. We determined that the mechanism of response to cisplatin treatment was dependent mitotic processes, where Brca2 is known to play a role in mediating abscission in the final stages of cell division. These data suggest a novel mechanism of sensitivity for BRCA2-mutant tumors and provide preclinical support for specific chemotherapeutic agents in PDA patients with BRCA2 mutations. Citation Format: Barbara Orelli, Hans Carlo Maurer, Carmine F. Palermo, Stephen A. Sastra, Kenneth P. Olive. Selective lethality of cisplatin in pancreatic cancer is dependent on mitotic functions of BRCA2 [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr PR12.