Tumorigenic effect of TERT and its potential therapeutic target in NSCLC (Review)

Abstract

Non-small cell lung cancer (NSCLC), which accounts for ~85% of all lung cancer cases, is commonly diagnosed at an advanced stage and has a high patient mortality rate. Despite the increasing availability of treatment strategies, the prognosis of patients with NSCLC remains poor, with a low 5-year survival rate. This poor prognosis may be associated with the tumor heterogeneity of NSCLC, as well as its acquisition and intrinsic resistance to therapeutic drugs. It has been suggested that combination therapy with telomerase inhibition may be an effective strategy for the treatment of drug-sensitive and drug-resistant types of cancer. Telomerase is the key enzyme for cell survival, and ~90% of human cancers maintain telomeres by activating telomerase, which is driven by the upregulation of telomerase reverse transcriptase (TERT). Several mechanisms of telomerase reactivation have been described in a variety of cancer types, including TERT promoter mutation, epigenetic modifications via a TERT promoter, TERT amplification, and TERT rearrangement. The aim of the present study was to comprehensively review telomerase activity and its association with the clinical characteristics and prognosis of NSCLC, as well as analyze the potential mechanism via which TERT activates telomerase and determine its potential clinical application in NSCLC. More importantly, current treatment strategies targeting TERT in NSCLC have been summarized with the aim to promote discovery of novel strategies for the future treatment of NSCLC. Contents1. Introduction 2. Telomerase activity and hTERT mRNA in NSCLC 3. Regulatory mechanism of TERT regarding telomerase activity in NSCLC 4. Current telomerase-targeted therapies in NSCLC 5. Discussion 6. Conclusions

TERT Mutations in Non–Small Cell Lung Cancer: Clinicopathologic Features and Prognostic Implications

“…11 TERT point mutation, amplification, rearrangement, and epigenetic modification through the TERT promoter can regulate human TERT (hTERT) expression level, activate telomerase, maintain telomere length, and promote tumor growth. 12 Studies have found that TERT co-mutation with other genes mutations can increase the degree of malignancy of tumors, consistent with an anticipated poor prognosis. 13 Co-occurring genomic alterations have emerged as core molecular and clinical heterogeneity determinants in oncogenedriven lung cancer subtypes.…”

Signature reversion of three disease‐associated gene signatures prioritizes cancer drug repurposing candidates

“…We were interested in investigating the GO term groups that differed between the disease‐associated gene signatures, as these may drive the differences in the drug candidate sets. Many of the distinct GO term groups are associated with disease progression or response to therapy [ 47 , 48 , 49 , 50 , 51 , 52 , 53 ]. For example, the LIHC disease‐associated gene signature from the DESeq2 approach contained up‐regulated GO terms unique for the cell differentiation subgroup compared to the other two signatures (Fig.…”

Signature reversion of three disease-associated gene signatures prioritizes cancer drug repurposing candidates

“…Many of these distinct GO term groups are associated with disease progression or response to therapy. [47][48][49][50][51][52][53] Thus, each approach for defining disease-associated gene signature identified different aspects of cancer biology to target via signature reversion.…”