GNS561, a clinical-stage PPT1 inhibitor, is efficient against hepatocellular carcinoma via modulation of lysosomal functions

Abstract

Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer. Autophagy inhibitors have been extensively studied in cancer but, to date, none has reached efficacy in clinical trials. In this study, we demonstrated that GNS561, a new autophagy inhibitor, whose anticancer activity was previously linked to lysosomal cell death, displayed high liver tropism and potent antitumor activity against a panel of human cancer cell lines and in two HCC in vivo models. We showed that GNS561, which is an effective lysosomotropic agent, can reach and inhibit its enzyme target, palmitoyl-protein thioesterase 1, resulting in lysosomal unbound Zn2+ accumulation, impairment of cathepsin activity, blockage of autophagic flux, altered location of mTOR, lysosomal membrane permeabilization, caspase activation and cell death. Accordingly, GNS561, currently tested in a global Phase 1b/2a clinical trial against primary liver cancer, represents a promising new drug candidate and a hopeful therapeutic strategy in cancer treatment.

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

“…The effectiveness of GNS561 to kill both tumor bulk cells and CSCs can be explained by its capacity to inhibit autophagy and lysosomal functions and to disrupt lysosomes [14]. In fact, once established, tumors require an uninterrupted nutritional supply for maintaining their proliferative needs in stressful conditions such as hypoxia, nutrient and growth factor starvation, and oxidative and metabolic stress [17].…”

“…Further research will be necessary to better understand the underlying mechanisms implicated in GNS561 activity against CSCs. It would be interesting to evaluate whether GNS561 treatment results from GNS561-induced inhibition of PPT1 and the mTOR pathway and lysosomal zinc sequestration in CSCs, as demonstrated in whole tumors [14]. In fact, knockout of PPT1 in tumor cells inhibited tumor growth, tumorsphere formation and tumorigenesis in vivo [48], suggesting that PPT1 may be implicated in CSC maintenance.…”

“…We previously reported that GNS561, a new lysosomotropic molecule with high hepatic tropism, was efficient against intrahepatic cholangiocarcinoma and HCC [14,15]. Based on robust preclinical data, the potential use of GNS561 against primary and secondary liver cancers was evaluated in a global phase 1b clinical trial (NCT03316222), which was recently successful [16].…”

“…Based on robust preclinical data, the potential use of GNS561 against primary and secondary liver cancers was evaluated in a global phase 1b clinical trial (NCT03316222), which was recently successful [16]. Regarding its mode of action, GNS561 was shown to suppress cancer cell growth via the induction of apoptosis resulting from inhibition of palmitoyl-protein thioesterase 1 (PPT1) activity, lysosomal unbound Zn 2+ accumulation, impairment of cathepsin activity, blockage of autophagic flux, altered localization of mTOR, lysosomal membrane permeabilization and caspase activation [14].…”

Extracellular Acidification Induces Lysosomal Dysregulation

“…GNS561, targeting PPT1 that has been shown to have significant antitumor activity against hepatocellular carcinoma in models is in current clinical trials. It has been shown to alter Zn + accumulation, cathepsin activity, autophagic flux, and mTOR localization [ 67 ]. With all this being said, there is some concern about the targeting of lysosomes by therapeutics due to the diversity and importance of proper lysosomal function.…”