Poster Presentation 37th Lorne Cancer Conference 2025

CK2 inhibition as a promising treatment for chemotherapy resistant pancreatic ductal adenocarcinoma (#246)

Diana Schuhmacher 1 2 , Aji Istadi 1 2 , Beatrice Zema 1 , Dannielle Upton 1 2 , Deanna Miller 1 2 , Emer Cahill 1 , Henry Barraclough-Franks 1 , Inna Navarro 1 , Johana Luhur 1 2 , Silvia Lombardi 1 , Sofia Omari 1 2 , Yasir Mahmood 1 , Diego Chacon Fajardo 1 2 , Thomas Cox 1 2 , Roger Daly 3 , Marina Pajic 1 2
  1. The Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
  3. Department of Biochemistry and Molecular Biology, Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia

Pancreatic ductal adenocarcinoma (PDAC) will become the 2nd most common cause of cancer-related death by 2030, with a 12.5% five-year survival rate. Inadequate early detection methods mean most PDAC patients are diagnosed with advanced/metastatic disease ineligible for surgical resection. Many patients develop resistance to the current standard of care chemotherapies, and while immunotherapy is proving promising for other solid cancers, the immune “cold” tumour microenvironment of PDAC results in a near universal resistance to immune checkpoint blockade1,2. Thus, understanding the mechanisms that drive therapy resistance, and identifying treatment strategies to circumvent these resistances, is an important step in the fight against PDAC.

The serine/threonine kinase CK2 is a major regulator of numerous signalling pathways and cellular functions in normal and disease states. CK2 is upregulated in numerous cancers including PDAC, especially chemotherapy-resistant PDAC cells3,4. Additionally, inhibition of CK2 upregulates immune response in mouse models of PDAC5. CK2 inhibition also increases cancer cell sensitivity to chemotherapy by inhibiting DNA damage repair response6. Using the first-in-class, CK2-selective inhibitor CX-4945/Silmitasertib, shown to be safe and well-tolerated in phase I/II clinical trials for cholangiocarcinoma, medulloblastoma, and basal cell carcinoma7, and well defined in vitro and in vivo models of PDAC validated in our laboratory, we aim to investigate the impact of CK2 inhibition on PDAC tumorigenesis, metastasis, chemoresistance, and immune infiltration. In vitro, we have observed varied sensitivity to CK2 inhibition across varying patient-derived PDAC cell lines, and inhibition of cancer cell invasion into a fibroblast-remodelled collagen matrix, prompting further investigation into cancer-stromal cell interactions. Investigation of CK2 expression across a microarray of patient-derived xenograft tumours showed varying subcellular localisation of CK2 between cytoplasmic, nuclear, and endosomal compartments, while examination of chemoresistant tumours revealed an increase in nuclear localisation of CK2. Notably, nuclear accumulation of CK2 is a reliable predictor of poor prognosis8. We hypothesise that inhibition of CK2 will reduce metastasis and improve overall survival in in vitro and in vivo models of PDAC by sensitising PDAC cells to the latest clinically used chemotherapies by inhibiting CK2-driven DNA damage repair pathways, and promoting activation of the existing immune system.

  1. Bear, A. S., Vonderheide, R. H. & O'Hara, M. H. Challenges and Opportunities for Pancreatic Cancer Immunotherapy. Cancer Cell 38, 788-802, doi:https://doi.org/10.1016/j.ccell.2020.08.004 (2020).
  2. Parkin, A. et al. The Evolving Understanding of the Molecular and Therapeutic Landscape of Pancreatic Ductal Adenocarcinoma. Diseases 6, doi:10.3390/diseases6040103 (2018).
  3. Kreutzer, J. N., Ruzzene, M. & Guerra, B. Enhancing chemosensitivity to gemcitabine via RNA interference targeting the catalytic subunits of protein kinase CK2 in human pancreatic cancer cells. BMC Cancer 10, 440, doi:10.1186/1471-2407-10-440 (2010).
  4. Liu, Z.-D. et al. CSNK2A1 confers gemcitabine resistance to pancreatic ductal adenocarcinoma via inducing autophagy. Cancer Letters 585, doi:10.1016/j.canlet.2024.216640 (2024).
  5. Nelson, N. et al. Apigenin: Selective CK2 inhibitor increases Ikaros expression and improves T cell homeostasis and function in murine pancreatic cancer. PLoS One 12, e0170197, doi:10.1371/journal.pone.0170197 (2017).
  6. Siddiqui-Jain, A. et al. CK2 inhibitor CX-4945 suppresses DNA repair response triggered by DNA-targeted anticancer drugs and augments efficacy: mechanistic rationale for drug combination therapy. Mol Cancer Ther 11, 994-1005, doi:10.1158/1535-7163.MCT-11-0613 (2012).
  7. Bancet, A. et al. Cancer selective cell death induction by a bivalent CK2 inhibitor targeting the ATP site and the allosteric alphaD pocket. iScience 27, 108903, doi:10.1016/j.isci.2024.108903 (2024).
  8. Homma, M. K. et al. Intracellular localization of CK2α as a prognostic factor in invasive breast carcinomas. Cancer Sci 112, 619-628, doi:10.1111/cas.14728 (2021).