Abstract B005: Exploiting chemotherapy-induced vulnerabilities in pancreatic ductal adenocarcinoma (PDAC) to improve treatment outcomes

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of cancer, with a five-year survival rate of just 13%1. Over 80% of patients present with advanced, metastatic disease and are, therefore, ineligible for surgical resection. Systemic chemotherapy, particularly FOLFIRINOX, offers modest survival benefits (median 11.1 months vs. 6.8 months with gemcitabine)2, however, we and others have shown that co-targeting pancreatic cancer tumours in combination with chemotherapy can improve outcomes in pre-clinical models3-7. Thus, this project aims to uncover the mechanisms by which PDAC acquires resistance to FOLFIRINOX, and to identify strategies to restore or enhance treatment sensitivity. To model clinical treatment dynamics, we have subjected orthotopically implanted patient-derived xenografts (PDXs) from the Australian Pancreatic Cancer Matrix Atlas (APMA)8 to 11–15 rounds of FOLFIRINOX or vehicle in vivo. Similarly, orthotopic tumours derived from the KPC mouse model (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre) have undergone 5–6 cycles of treatment. Tumours were then profiled using data-independent acquisition (DIA) mass spectrometry and RNA sequencing to identify chemotherapy-induced vulnerabilities in these patient-derived tumours. This dual analysis revealed a strong DNA repair signature in the chemotherapy-treated PDXs, and I am now investigating the top candidates as co-targets alongside FOLFIRINOX. In parallel, we have established matched treatment-naïve and FOLFIRINOX-treated patient-derived cell lines (PDCLs) and KPC tumour cell lines. These models will be used to further validate candidate resistance pathways through genetic and pharmacological approaches. Functional assays including 3D organotypic matrix cultures will assess tumour cell invasion and drug response3-7. Furthermore, in vivo subcutaneous and orthotopic models, coupled with intravital imaging and biosensors, will allow dynamic monitoring of our co-targeting strategy in live primary pancreatic tumours and metastatic sites (eg. liver)3-7. Overall, by identifying resistance-associated proteins and pathways, this work aims to inform the development of co-targeting approaches that can restore and/or enhance the therapeutic efficacy of FOLFIRINOX in PDAC. References: 1. Siegel et al. CA: A Cancer Journal for Clinicians 75, 10-45 (2025). 2. Conroy et al. New England Journal of Medicine 364, 1817-1825 (2011). 3. Vennin et al. Science Translational Medicine 9 9(384):eaai8504 (2017). 4. Vennin et al. Nature Communications 10, 3637 (2019). 5. Murphy et al. Science Advances 7, eabh0363 (2021). 6. Chitty et al. Nature Cancer 4, 1326–1344 (2023) 7. Pereira et al. Science Advances 10, eadl1197 (2024). 8. Australian Pancreatic Cancer Matrix Atlas (APMA), https://www.pancreaticcancer.net.au/apma/ Citation Format: Brooke A. Pereira, Katie Gordon, Victoria M. Tyma, Ying Fei Liew, Alice M H. Tran, Anna E. Howell, Shona Ritchie, Kendelle J. Murphy, Marina Pajic, Thomas R. Cox, David Herrmann, Paul Timpson. Exploiting chemotherapy-induced vulnerabilities in pancreatic ductal adenocarcinoma (PDAC) to improve treatment outcomes [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr B005.