Synergistic antitumor activity of sorafenib and the NUPR1 inhibitor LZX-2-73 in multiple cancer models.

Combination therapy in cancer treatment offers significant potential to overcome drug resistance, enhance efficacy, reduce toxicity, and expand drug indications. sorafenib, an FDA-approved multi-targeted kinase inhibitor, has demonstrated effectiveness across various cancers but currently lacks approved combination therapies. Recently, we identified LZX-2-73 as a promising drug candidate with potent anticancer activity, targeting the nuclear protein 1 (NUPR1), an emerging and promising target in cancer therapy. In this study, we report that the combination of the NUPR1 inhibitor LZX-2-73 with sorafenib produces strong synergistic anticancer effects in various cancer cell lines as well as in primary pancreatic ductal adenocarcinoma (PDAC) organoids. This combination significantly enhanced lactate dehydrogenase (LDH) release and caspase 3/7 activity, markedly induced ROS accumulation, reduced the reduced/oxidized glutathione ratio, and increased the accumulation of malondialdehyde (MDA) and lipid hydroperoxides. Collectively, the combination of LZX-2-73 and sorafenib led to a substantial increase in cell death due to massive oxidative stress. Additionally, in a pancreatic cancer xenograft mouse model, the combination of LZX-2-73 and sorafenib exhibited a synergistic anticancer effect, effectively inhibiting tumor growth. In summary, this study provides valuable insights into enhancing the anticancer activity of NUPR1 inhibitors through combination with sorafenib, offering a promising new avenue for cancer therapy and opening new indications.