Poster Presentation 36th Lorne Cancer Conference 2024

Therapeutic potential of targeting epigenetic deregulation in pancreatic cancer (#222)

Johana Luhur 1 2 , Diego Chacon Fajardo 1 2 , Benjamin McLean 1 2 , Aji Istadi 1 2 , Emer Cahill 1 , Silvia Lombardi 1 , Yasir Mahmood 1 , Cathy Wang 1 , Australian Pancreatic Cancer Genome Initiative (APGI) 3 , Clare Stirzaker 1 2 , Sean Porazinski 1 2 , Marina Pajic 1 2
  1. The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales, Australia
  2. St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia
  3. International Cancer Genome Consortium, (ICGC)

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with multiple genetic and epigenetic alterations and significant heterogeneity. Standard-of-care chemotherapies only benefit small proportion of patients in unselected populations, thus, a more personalised treatment is needed. Arginine methylation is a universal post-translational modification catalysed by protein arginine methyltransferases (PRMTs). Inhibiting PRMTs has recently emerged as a potential therapeutic strategy as most tumours, including PDAC, overexpress PRMTs, particularly PRMT1 and PRMT5 [1]. High expression of PRMT5 promotes cancer cell proliferation and is associated with poor prognosis in PDAC [2]. 

To investigate potential biomarkers of cancer cell sensitivity to PRMT5 inhibition, 21 established patient-derived cell lines (PDCLs) of PDAC and murine KPC (LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre), KPflC (LSL-KrasG12D/+; LSL-Trp53loxP/+; Pdx1-Cre), and KC (LSL-KrasG12D/+; Pdx1-Cre) cells were screened in vitro using cytotoxicity assays with various concentration of SAM-competitive (LLY-283) and substrate-competitive (GSK-3326595) PRMT5 inhibitors. A broad range of sensitivity to PRMT5 inhibition was observed across different cell lines which did not correlate with previously reported biomarkers, such as MTAP status [3], p53 status [4], and MYC expression [5]. Next, we assessed synergy of PRMT5 inhibitors in combination with targeted agents and chemotherapies using Combination Index (CI) scores. We identified MAT2A and DNA damaging agents (including PARP inhibitors and selected chemotherapies) to be synergistic (CI<0.8) to additive (CI=1) with PRMT5 inhibitors in a range of PDAC models, irrespective of MTAP and p53 status. This suggests that PRMT5 sensitivity goes beyond MTAP and p53 status, with new biomarkers yet to be discovered. Further, using 3D tumour cell-cancer associated fibroblast (CAF) co-culture assays, we showed no direct effects of PRMT5 targeting on CAF contractility and matrix remodelling; however, inhibition of PRMT5 significantly reduced cancer cell invasion in 3D model.

Our ongoing work focuses on understanding the biological determinants behind PRMT5 inhibitor response, the mechanisms behind synergy with DNA damaging agents, and in vivo tumour and functional studies to determine the optimal combination treatment strategies for PRMT5-based therapy in PDAC.

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