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GNS561, a new lysosomotropic small molecule, for the treatment of intrahepatic cholangiocarcinoma

Abstract : Among the acquired modifications in cancer cells, changes in lysosomal phenotype and functions are well described, making lysosomes a potential target for novel therapies. Some weak base lipophilic drugs have a particular affinity towards lysosomes, taking benefits from lysosomal trapping to exert anticancer activity. Here, we have developed a new lysosomotropic small molecule, GNS561, and assessed its activity in multiple in vitro intrahepatic cholangiocarcinoma models (HuCCT1 and RBE cell lines and patient-derived cells) and in a chicken chorioallantoic membrane xenograft model. GNS561 significantly reduced cell viability in two intrahepatic cholangiocarcinoma cell lines (IC 50 of 1.5 ± 0.2 μM in HuCCT1 and IC 50 of 1.7 ± 0.1 μM in RBE cells) and induced apoptosis as measured by caspases activation. We confirmed that GNS561-mediated cell death was related to its lysosomotropic properties. GNS561 induced lysosomal dysregulation as proven by inhibition of late-stage autophagy and induction of a dose-dependent build-up of enlarged lysosomes. In patient-derived cells, GNS561 was more potent than cisplatin and gemcitabine in 2/5 and 1/5 of the patient-derived cells models, respectively. Moreover, in these models, GNS561 was potent in models with low sensitivity to gemcitabine. GNS561 was also efficient in vivo against a human intrahepatic cholangiocarcinoma cell line in a chicken chorioallantoic membrane xenograft model, with a good tolerance at doses high enough to induce an antitumor effect in this model. In summary, GNS561 is a new lysosomotropic agent, with an anticancer activity against intrahepatic cholan-giocarcinoma. Further investigations are currently ongoing to fully elucidate its mechanism of action.
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Submitted on : Monday, April 20, 2020 - 11:51:55 AM
Last modification on : Friday, August 5, 2022 - 3:44:07 PM




Sonia Brun, Firas Bassissi, Cindy Serdjebi, Marie Novello, Jennifer Tracz, et al.. GNS561, a new lysosomotropic small molecule, for the treatment of intrahepatic cholangiocarcinoma. Investigational New Drugs, Springer Verlag, 2019, 37 (6), pp.1135-1145. ⟨10.1007/s10637-019-00741-3⟩. ⟨hal-02463196⟩



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