Jorunnamycin A induces apoptosis in pancreatic ductal adenocarcinoma cells, spheroids, and patient-derived organoids by modulating KRAS-mediated survival pathways.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a poor prognosis, frequently driven by oncogenic KRAS mutations. Among these, KRAS G12D is the most prevalent, contributing to chemoresistance and limiting the efficacy of current therapeutic strategies. This study investigates the therapeutic potential of jorunnamycin A (JA), a bioactive compound derived from the marine sponge Xestospongia, in PDAC. Molecular docking analyses were performed to assess JA's binding affinity for various KRAS protein variants. The synergistic effects of JA in combination with standard chemotherapeutic agents were evaluated using the Bliss independence model in pancreatic cancer cell lines and patient-derived PDAC organoids harboring distinct KRAS mutations. Furthermore, western blot analysis was performed to examine the impact the molecular mechanisms underlying JA's anticancer activity. JA demonstrated potent anticancer activity against PDAC cells, irrespective of their KRAS mutation status. In silico molecular docking and protein suppression studies indicated a strong binding affinity between JA and KRAS G12D. Synergistic interactions between JA and various PDAC chemotherapeutic agents, including oxaliplatin, SN-38, paclitaxel, 5-fluorouracil, and gemcitabine, were observed using the Bliss independence model. Notably, co-treatment with JA at a 10-fold lower concentration significantly enhanced the cytotoxicity of oxaliplatin, reducing its IC₅₀ values around tenfold. This synergistic impact was further validated in both KRAS G12D spheroids and patient-derived PDAC organoids harboring KRAS G12D and other KRAS variants. Mechanistically, the JA-oxaliplatin combination enhanced caspase-3/7 activation, suppressed key KRAS-mediated survival pathways (STAT3, B/C-RAF, AKT, and ERK), and led to the downregulation of anti-apoptotic proteins (MCL-1 and BCL-2). These findings highlight JA as a promising therapeutic candidate for PDAC, particularly in the context of KRAS G12D-driven tumors. Further investigations into its pharmacokinetics and clinical feasibility are warranted to explore its full potential in PDAC treatment.