Oral Presentation Hunter Cell Biology Meeting 2025

Identifying PCSK9 as a potential therapeutic co-target in metastatic pancreatic ductal adenocarcinoma, through integrated transcriptomic and proteomic analysis. (120053)

Shona Ritchie 1 2 , Victoria Tyma 1 2 , Shanna Hafiz 1 2 , Cecilia Chambers 1 2 , Kendelle Murphy 1 2 , Ying Fei Liew 1 2 , Victoria Lee 1 2 , Julia Hartmaan 1 2 , Alice Tran 1 2 , Deborah Barkauskas 1 2 , Angela Fontaine-Titley 1 2 , Julia Yin 1 2 , Sai Vara Prasad Chiiti 3 , Australian Pancreatic Genome Initiative 1 2 , Australian Pancreatic Cancer Matrix Atlas 1 2 , Susan Clark 1 2 , Benjamin Parker 4 , Max Nobis 5 , Owen Sansom 6 7 , Jennifer P Morton 6 7 , Lisa Horvarth 2 8 , Suresh Mathivanan 3 , Ruth Pidsley 1 2 , David Herrmann 1 2 , Thomas Cox 1 2 , Marina Pajic 1 2 , Brooke Pereira 1 2 , Paul Timpson 1 2
  1. St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
  2. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  3. Biochemistry and Genetics, La Trobe University, Melbourne, VIC, Australia
  4. School of Biomedical Sciences, University of Melbourne, Melbourne, VIC, Australia
  5. Intravital Imaging Expertise Center, VIB-KU Leuven Center for Cancer Biology, Leuven, Belgium
  6. Cancer Research UK Beatson Institute, Glasgow, Scotland, UK
  7. Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland
  8. Chris O’Brien Lifehouse, Sydney, NSW, Australia

Pancreatic ductal adenocarcinoma cancer (PDAC) is a lethal malignancy with high incidences of metastases and therapy resistance[1]. Using RNA sequencing and mass spectrometry proteomics, we robustly profiled the transcriptome, secretome and exosome profile of PDAC tumours from the highly-metastatic KPC[2] vs. the poorly-metastatic KPflC[3] GEMM. This revealed that proprotein convertase subtilisin/kexin type 9 (PCSK9) is significantly overexpressed and secreted by metastatic PDAC tumours.  

 

PCSK9 is canonically known to have a role in regulating cholesterol uptake by degrading low density lipoprotein receptors (LDLR)[4], but has recently been described to have diverse functions in cancer promotion, including the regulation of proliferation[5], apoptosis[6] and immunosurveillance[7, 8]. Here, we show that PCSK9 is significantly upregulated by metastatic PDAC cells, confirmed by WB, ELISA, RT qPCR, and IHC analyses of KPC tumours. Additionally, IHC analyses of PDAC patient tumour microarrays from Australian Pancreatic Genome Initiative/International Cancer Genome Consortium clinical cohorts revealed that high PCSK9 is significantly associated with advanced disease and poorer survival, prompting us to explore PCSK9 as a clinically-relevant target.

 

As such, inhibition of PCSK9 was carried out in KPC cells during invasion of 3D-organotypic matrices. We show that inhibition of PCSK9 i) genetically and ii) pharmacologically significantly impedes cancer cell invasion. Utilising PCSK9 inhibitors, such as the clinically-approved antibody evolocumab (Amgen®) and the small molecule inhibitor PF846 (Pfizer), we demonstrate a significant improved response to standard-of-care chemotherapy gemcitabine/Abraxane, via decreased ki67, increased cleaved-caspase 3 and increased yH2AX staining.

 

In vivo, PCSK9 inhibition using i) evolocumab ± gem/Ab and ii) PF846 ± gem/Ab significantly decreased tumour volume and increased survival in subcutaneous models. In intrasplenic experimental models of metastasis, PCSK9 inhibition via PF846 significantly decreased metastasis compared to vehicle, and further reduced metastasis compared to gem/Ab alone. Multiphoton microscopy of FUCCI cell cycle reporter-expressing tumours demonstrated significant cell cycle stalling at G2 with PCSK9 inhibitors ± gem/Ab, indicative of an enhanced chemotherapy response. Overall, this work identifies PCSK9 as a novel ‘druggable’ target and presents a potential opportunity to repurpose FDA/TGA-approved inhibitor evolocumab in PDAC.

 

References

  1. Siegel, R.L., et al. CA Cancer J Clin (2023)
  2. Hingorani, S.R., et al. Cancer Cell, (2005)
  3. Morton, J.P., et al. PNAS (2010)
  4. Abifadel, M., et al. Nature Genetics (2003)
  5. Wang, L., et al. Journal of Experimental & Clinical Cancer Research (2022)
  6. Xu, X., et al. Exp Ther Med (2017)
  7. Liu, X., et al. Nature (2020)
  8. Yuan, J., et al. Protein Cell (2022)