Inhibiting Glutamine-Dependent mTORC1 Activation Ameliorates Liver Cancers Driven by β-Catenin Mutations

Abstract

Highlights d mTORC1 activation is seen basally in pericentral hepatocytes because of Wnt/b-catenin d CTNNB1-mutated liver tumors are positive for GS and p-mTOR-S2448 d CTNNB1-mutated hepatocellular cancers are addicted to mTORC1 for metabolism d Targeting b-catenin-GS-mTORC1 axis in liver tumors may enable precision medicine

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

“…Glutamine synthase levels also affect mTORC1 activation. In liver cancer with mutations in β-catenin, levels of GS, a target of β-catenin, are increased and its disruption prevents mTOR phosphorylation at Ser2448, suggesting downregulation of mTOR activity [139]. In some cell types, in the absence of glutamine, cells utilize ammonia as an alternative nitrogen source.…”

Mammalian Target of Rapamycin Inhibitors, New Drugs for Beta‐Catenin–Mutated Hepatocellular Carcinomas?

“…The complexity of the Wnt/β‐catenin pathway combined with the ubiquitous nature of Wnt signaling complicate its blockade. Furthermore, very few agents have been developed that interfere with β‐catenin‐dependent gene transcription, rendering the CTNNB1 mutations clinically, mostly, “undruggable.” A study by Adebayo Michael et al, published in a recent issue of Cell Metabolism , reveals that in β‐catenin‐activated liver cancers the overexpression of the hepatic β‐catenin target gene, glutamine synthetase ( GLUL ) leads to activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway through accumulation of glutamine . These findings open the possibility that mTOR inhibitors could represent a strategy to treat the CTNNB1 ‐mutated HCC that represents almost 30%‐40% of HCC cases.…”

“…However, the mechanisms by which mTORC1 was activated following an increase in Wnt/β‐catenin activity were not investigated. Adebayo Michael et al showed, with different HCC mouse models bearing a constitutive activation of Wnt/β‐catenin signaling, that all the tumors stained positively for Glul and were also positive for phosphorylated (p‐) mTOR‐S2448, used in the study as a readout of mTOR activation . HCCs not activated for β‐catenin were not stained for p‐mTOR‐S2448.…”

“…The pioneering results described in the study of Adebayo Michael et al concern the identification of mTOR activation in the pericentral region of the normal adult liver . In the liver, hepatocytes are partitioned into three metabolic zones based on their function and location within the lobules of the zonated liver.…”

“…Overexpression of Glul in β‐catenin‐activated hepatocytes resulted in mTORC1 activation. Adebayo Michael et al demonstrate mTORC1 activation in pericentral hepatocytes that overexpressed Glul as a target of the physiological activation of Wnt/β‐catenin signaling (A) and in CTNNB1 ‐mutated HCC overexpressing GLUL (B). The study elegantly shows that mTORC1 activation resulted from glutamine accumulation and points to mTOR inhibitors as targeted therapy for CTNNB1 ‐mutated HCC.…”