Telomerase: a good target in hepatocellular carcinoma? An overview of relevant preclinical data

ABSTRACT

Introduction

The expression of telomerase reverse transcriptase (TERT) in liver is restricted to rare cells, that are able to replace senescent hepatocytes and regenerate tissue in response to hepatic damage, while becoming extinguished in differentiated progeny cells. TERT gene is permanently activated in liver neoplasms from the very early stage of the hepatocarcinogenesis mainly through the accumulation of genetic alterations, virus-related insertional mutagenesis and somatic mutations in the TERT promoter region. Several lines of evidence suggest that telomerase, beyond the canonical function of telomeres elongation, has multiple oncogenic activities in cancer cells and may represent a promising therapeutic target in hepatocellular carcinoma (HCC).

Areas covered

We review the mechanisms of activation of telomerase in HCC, the canonical and non-canonical functions of TERT as well as experimental strategies to directly target telomerase or to inhibit pathways associated with telomerase activity.

Expert opinion

TERT holoenzyme and telomerase components represent promising therapeutic targets in the treatment of liver malignancies. Several chemical agents and natural products known to alter telomerase activity are under evaluation for their potency to inhibit telomeres attrition in cirrhosis and TERT function in liver cancer. Therefore, this review outlines the current strategies pursued to suppress the multiple mechanisms of the major telomerase components in liver cancer.

KEYWORDS:

• Telomerase
• TERT
• Hepatocellular carcinoma
• TERT promoter
• Mutation
• Target therapy
• Telomerase inhibitor
• Small molecules
• Nucleoside analogues

Article highlights

• Telomerase activation is the earliest event in hepatocarcinogenesis, associated with progression and aggressiveness of HCC.

• TERT promoter mutations represent the most frequent genetic alterations in HCC with an overall frequency around 60%.

• Selective reactivation of the TERT gene in the vast majority of liver cancers, while remaining suppressed in normal cells, offers the potential to develop specific anticancer therapies that interfere with telomerase expression or activities.

• Novel functional molecules that either directly inhibit telomerase function or pathway elongation and non-canonical oncogenic activities of TERT are promising strategies for the treatment of TERT expressing tumors.

• Several agents have been evaluated in preclinical studies for their effect on telomerase inhibition and found efficient against cancer cells. However, newly developed molecules that selectively stabilize the G-quadruplex structures in TERT mutated promoters have yet to be tested in HCC-derived cell lines.

In addition, telomerase inhibitors may have a synergistic activity when combined with conventional or targeted therapies in many human cancers including HCC. More preclinical and clinical studies are needed to demonstrate the effect of combined drugs.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by a research grant funded by the Italian ministry of Health Ricerca Corrente L1/10.