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Pivotal role of mTOR signaling in hepatocellular carcinoma

Augusto Villanueva1, Derek Y Chiang, Pippa Newell

  • 1Mount Sinai Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.

Gastroenterology
|October 22, 2008
PubMed
Abstract

Insights

Aberrant mTOR signaling is common in hepatocellular carcinoma (HCC), linked to poor outcomes. Dual blockade of mTOR signaling with everolimus showed promising anti-tumor effects in preclinical models, supporting clinical trials for HCC treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Hepatology

Background:

  • Targeted therapies for hepatocellular carcinoma (HCC) require detailed pathway characterization.
  • The mechanistic target of rapamycin (mTOR) pathway is a key area for identifying novel therapeutic targets in HCC.

Purpose of the Study:

  • To evaluate mTOR signaling in human HCC.
  • To assess the antitumoral effects of dual blockade of the mTOR pathway.

Main Methods:

  • Integrated analysis of mutation, copy number, mRNA, and protein activation of the mTOR pathway in 351 human HCC samples.
  • Evaluation of dual mTOR blockade using everolimus and AEE788 in liver cancer cell lines and a xenograft model.

Main Results:

  • Aberrant mTOR signaling (p-RPS6) was found in 50% of HCC cases, associated with insulin-like growth factor pathway activation and epidermal growth factor up-regulation.
  • Chromosomal gains in RICTOR and positive p-RPS6 staining correlated with tumor recurrence.
  • Dual mTOR blockade with everolimus demonstrated decelerated tumor growth and increased survival in preclinical models, enhanced by epidermal growth factor blockade.

Conclusions:

  • MTOR signaling plays a critical role in HCC pathogenesis, with evidence for RICTOR involvement.
  • MTOR blockade using everolimus is effective in vivo against HCC.
  • These findings provide a strong rationale for targeting the mTOR pathway in clinical trials for HCC.

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