Abstract A056: Targeting the mutant p53 cancer cell secretome sensitizes tumors to gemcitabine/nab-paclitaxel chemotherapy and reduces metastasis in pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal and metastatic malignancy, with standard-of-care treatments, such as gemcitabine/nab-paclitaxel (GnP) offering limited improvement for patients with advanced disease. We and others have shown that co-targeting key factors in combination with chemotherapy can improve outcomes in preclinical models [1-5]. To identify pro-metastatic co-factors to target in conjunction with standard-of-care chemotherapies, we have assessed the cancer cell secretome, exosome proteome and transcriptome of PDAC cells derived from primary tumors from the poorly-metastatic p53-null KPflC, and highly-metastatic p53-mutant KPC genetically engineered mouse models [6,7]. Here, we identified 290 abundantly secreted proteins, with 12 of these demonstrating overlapping differential gene expression. We integrated this screen and identified serine protease proprotein convertase subtilisin/kexin type 9 (PCSK9) as upregulated in the metastatic p53-mutant setting. Known to regulate low-density lipoprotein receptors (LDLR) [8], PCSK9 has recently been reported to have additional roles in cancer, such as degradation of major histocompatibility class I (MHC I), and the regulation of proliferation, apoptosis and metastasis [9-14]. As such, we have further pursued its role in chemotherapy resistance and disease progression in PDAC. Analysis of patient cohorts, including the Australian Pancreatic Genome Initiative (APGI), revealed high expression of PCSK9 is associated with poorer clinical outcomes. To determine its functional role, we utilized genetic and pharmacological approaches to inhibit PCSK9 in combination with GnP. 3D organotypic matrix invasion assays, fluid-flow induced shear stress, and multiphoton imaging were used to assess the impact of PCSK9 depletion on disease progression. Combining PCSK9 inhibition alongside GnP chemotherapy significantly potentiated GnP cytotoxicity. Additionally, this combination strategy reduced metastases compared to chemotherapy alone. Overall, this work establishes preclinical evidence for novel co-targeting strategies that enhance therapeutic efficacy of standard-of-care therapies in PDAC. References: 1. Pereira and Ritchie et al. Sci Adv 2024; 10.1126/sciadv.adl1197 2. Murphy et al. Sci Adv 2021; 10.1126/sciadv.abh0363 3. Chou et al. Gut 2018; 10.1136/gutjnl-2017-315144 4. Vennin et al. Sci Transl Med 2017; 10.1126/scitranslmed.aai8504 5. Chitty et al. Nat Cancer 2023; 10.1038/s43018-023-00614-y 6. Hingorani et al. Cancer Cell 2005; 10.1016/j.ccr.2005.04.023 7. Morton et al. Proc Natl Acad Sci U S A 2010; 10.1073/pnas.0908428107 8. Abifadel et al. Nat Genet 2003; 10.1038/ 9. Yuan et al. Protein Cell 2021; 10.1007/s13238-021-00821-2 10. Liu et al. Nature 2020; 10.1038/s41586-020-2911-7 11. Rademaker et al. Nature 2025; 10.1038/s41586-025-09017 12. Mei et al. Cell 2025; 10.1016/j.cell.2024.11.009 14. Wong et al. Nat Comm 2022; 10.1038/s41467-022-31663-z