Abstract A031: Identification of therapeutic vulnerabilities in the subset of pancreatic ductal adenocarcinoma (PDAC) with homologous recombination deficiency

Abstract The genetic landscape of pancreatic ductal adenocarcinoma (PDAC) is characterized by mutations in the KRAS, TP53, CDKN2A and SMAD4 genes alongside multiple low-frequency mutations, which may offer opportunities for precision medicine. The success of poly-ADP-ribose polymerase (PARP) inhibitors in metastatic PDAC characterized by germline mutations in the Breast Cancer (BRCA) genes has led to the hypothesis that mutations in other BRCAness genes may sensitize PDAC to PARP inhibitors. To test this hypothesis, we used KPC mice as a backbone (Pdx1-Cre; LSL-KrasG12D/+; LSL-Trp53R172H/+) to generate models of PDAC driven by the loss of Ataxia Telangiectasia mutated (Atm, KPCA) or Brca1 (KPCB). Loss of Atm or Brca1 resulted in homologous recombination deficiency and genomic instability in vivo. In vitro cultures of KPCA and KPCB PDAC cells had higher numbers of micronuclei and were more radiosensitive than KPC cells. Next, we performed bulk and single-cell RNA sequencing to identify therapeutic vulnerabilities associated with Atm or Brca1 loss. We found that loss of Atm upregulated ATR signaling, suggesting ATR as a therapeutic target in KPCA mice. In agreement, ATR inhibition improved the survival of KPCA mice, with evidence of tumor growth delay. However, though PARP inhibition significantly improved the survival of KPCB mice, with delayed tumor growth, it was ineffective in KPCA mice. In addition, transcriptomic analysis showed an enrichment of immune cells in KPCB PDAC compared to KPC and KPCA PDAC. Notably, we found greater levels of STING signaling, a more diverse and abundant cytokine profile and more CD8 T cells in KPCB PDAC, suggesting sensitivity to immune checkpoint blockade (ICB). However, ICB was ineffective in KPCB mice as a single agent or in combination with PARP inhibition. Based on our transcriptomic data, we hypothesized that boosting antigen priming using a CD40 agonist (CD40a) in combination with FLT3-L may improve ICB efficacy in our mouse models of BRCAness. Immunotherapy consisting of combined ICB, CD40a and FLT-3L had little efficacy in either KPCA or KPCB mice. However, ATR inhibition improved the efficacy of combined ICB, CD40a and FLT-3L in KPCA mice, as indicated by increased CD8 T cell infiltration in the tumor, delayed tumor growth and longer survival. In contrast, we found that PARP inhibition combined with ICB, CD40a and FLT-3L was ineffective in KPCB mice. In summary, we present evidence to suggest that PDAC characterized by BRCAness is not a homogeneous group with respect to sensitivity to PARP inhibition, composition of the tumor microenvironment and response to immunotherapy. We highlight ATM loss as a potential predictive biomarker of ATR inhibitor efficacy and immunotherapy in PDAC. Future directions include the evaluation of inflammation as a therapeutic vulnerability in murine PDAC with loss of Brca1. Ultimately, we aim to inform clinical trials to refine precision medicine of PDAC characterized by BRCAness. Citation Format: Mathias Tesson, Kay Kong, Peter Repsicak, Aldo Bader, Ya-Ching Hsieh, Craig Nourse, Kristina Kirschner, Crispin Miller, Ed Roberts, David Chang, Jen Morton. Identification of therapeutic vulnerabilities in the subset of pancreatic ductal adenocarcinoma (PDAC) with homologous recombination deficiency abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84 (17 Suppl₂): Abstract nr A031.