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

作者：Hnin Ei Ei Khine, Utid Suriya, Thanyada Rungrotmongkol, Supakarn Chamni, Yanxi Lu, Alan Bénard, Bin Lan, Debabrata Mukhopadhyay, David K. Chang, Andrew V. Biankin, Regine Schneider‐Stock, Robert Grützmann, Rungroch Sungthong, Christian Pilarsky, Chatchai Chaotham · 发表于：Scientific Reports · 年份：2025 · DOI：10.1038/s41598-025-95766-5 · 被引用次数：5 · 研究领域：Marine Sponges and Natural Products、Enzyme function and inhibition、PI3K/AKT/mTOR signaling in cancer

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 IC 50 values around tenfold. Thi...