GNS561, a New Autophagy Inhibitor Active against Cancer Stem Cells in Hepatocellular Carcinoma and Hepatic Metastasis from Colorectal Cancer

• Published in: Journal of Cancer Vol. 12; no. 18; pp. 5432 - 5438
• Main Authors: Brun, Sonia, Pascussi, Jean-Marc, Gifu, Elena Patricia, Bestion, Eloïne, Macek-Jilkova, Zuzana, Wang, Guanxiong, Bassissi, Firas, Mezouar, Soraya, Courcambeck, Jérôme, Merle, Philippe, Decaens, Thomas, Pannequin, Julie, Halfon, Philippe, Caron de Fromentel, Claude
• Format: Journal Article
• Language: English
• Published: Australia Ivyspring International Publisher Pty Ltd 01-01-2021; Ivyspring International Publisher
• Subjects: Apoptosis; Autophagy; Cancer therapies; Chemotherapy; Colorectal cancer; Experiments; Genotype & phenotype; Laboratory animals; Liver cancer; Medical prognosis; Metabolism; Metastasis; Normal distribution; Population; Radiation therapy; Research Paper; Software; Stem cells; liver cancer; colorectal cancer; cancer stem cell; GNS561; lysosome; therapy
• ISSN: 1837-9664; 1837-9664
• DOI: 10.7150/jca.58533

Patients with advanced hepatocellular carcinoma (HCC) or metastatic colorectal cancer (mCRC) have a very poor prognosis due to the lack of efficient treatments. As observed in several other tumors, the effectiveness of treatments is mainly hampered by the presence of a highly tumorigenic sub-population of cancer cells called cancer stem cells (CSCs). Indeed, CSCs are resistant to chemotherapy and radiotherapy and can regenerate the tumor bulk. Hence, innovative drugs that are efficient against both bulk tumor cells and CSCs would likely improve cancer treatment. In this study, we demonstrated that GNS561, a new autophagy inhibitor that induces lysosomal cell death, showed significant activity against not only the whole tumor population but also a sub-population displaying CSC features (high ALDH activity and tumorsphere formation ability) in HCC and in liver mCRC cell lines. These results were confirmed
in HCC from a DEN-induced cirrhotic rat model in which GNS561 decreased tumor growth and reduced the frequency of CSCs (CD90
CD45
). Thus, GNS561 offers great promise for cancer therapy by exterminating both the tumor bulk and the CSC sub-population. Accordingly, a global phase 1b clinical trial in liver cancers was recently completed.