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

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

  • Cell Death Dis. 2025 Nov 17;16(1):839. doi: 10.1038/s41419-025-08178-8.
Xi Liu # 1 2,  Matías Estaras # 1,  Emma Cosialls 1,  Ling Peng 2,  Patricia Santofimia-Castaño 3,  Juan Iovanna 4 5 6
Affiliations

Affiliations

  • 1 Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Translational Research and Therapeutic Targets in Pancreatic Cancer, Marseille, France.
  • 2 Aix-Marseille Université, CNRS, Centre Interdisciplinaire de Nanoscience de Marseille, UMR 7325, Parc Scientifique et Technologique de Luminy, Equipe labélisée Ligue Nationale contre le cancer, Marseille, France.
  • 3 Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Translational Research and Therapeutic Targets in Pancreatic Cancer, Marseille, France. [email protected].
  • 4 Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Translational Research and Therapeutic Targets in Pancreatic Cancer, Marseille, France. [email protected].
  • 5 Hospital de Alta Complejidad El Cruce, Florencio Varela, Buenos Aires, Argentina. [email protected].
  • 6 University Arturo Jauretche, Florencio Varela, Buenos Aires, Argentina. [email protected].
  • # Contributed equally.
PMID: 41249113 DOI: 10.1038/s41419-025-08178-8
Abstract

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.

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