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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

BACKGROUND Non-small-cell lung cancer (NSCLC) has the highest morbidity and mortality rates among all malignant tumor types. Although therapies targeting the mutated genes such as KRAS have been used in the clinic for many years, the prognosis remains poor. Therefore, it is necessary to further study the aberrant expression or mutation of non-target genes affecting the survival and prognosis. AIM To explore the impact of simultaneous abnormalities of multiple genes on the prognosis and survival of patients. METHODS We used R packages to analyze gene expression data and clinical data downloaded from The Cancer Genome Atlas (TCGA) database. We also collected samples from 85 NSCLC patients from the First People’s Hospital of Jingzhou City and retrospectively followed the patients. Multivariate Cox regression analysis and survival analysis were performed. RESULTS Analysis of gene expression data from TCGA revealed that the overexpression of the following single genes affected overall survival: TP53 ( P = 0.79), PTEN ( P = 0.94), RB1 ( P = 0.49), CTNNB1 ( P = 0.24), STK11 ( P = 0.32), and PIK3CA ( P = 0.013). However, the probability of multiple genes ( TP53 , PTEN , RB1 , and STK11 ) affecting survival was 0.025. Retrospective analysis of clinical data revealed that sex (hazard ratio [HR] = 1.29; [95%CI: 0.64-2.62]), age (HR = 1.05; [95%CI: 1.02-1.07]), smoking status (HR = 2.26; [95%CI: 1.16-4.39]), tumor histology (HR = 0.58; [95%CI: 0.30-1.11]), cancer stage (HR = 16.63; [95%CI: 4.8-57.63]), epidermal growth factor receptor ( EGFR ) mutation (HR = 1.82; [95%CI: 1.05-3.16]), abundance (HR = 4.95; [95%CI: 0.78-31.36]), and treatment with tyrosine kinase inhibitors (TKIs) (HR = 0.58; [95%CI: 0.43-0.78]) affected patient survival. Co-occurring mutations of TP53 , PTEN , RB1 , and STK11 did not significantly affect the overall survival of patients receiving chemotherapy ( P = 0.96) but significantly affected the overall survival of patients receiving TKIs ( P = 0.045). CONCLUSION Co-occurring mutation or overexpression of different genes has different effects on the overall survival and prognosis of NSCLC patients. Combined with TKI treatment, the co-occurring mutation of some genes may have a synergistic effect on the survival and prognosis of NSCLC pa...

Anaplastic lymphoma kinase (ALK) inhibitors have been shown to be effective in treating patients with ALK-positive non-small cell lung cancer (NSCLC), and crizotinib, ceritinib and alectinib have been approved as clinical first-line therapeutic agents. The availability of these inhibitors has also largely changed the treatment strategy for advanced ALK-positive NSCLC. However, patients still inevitably develop resistance to ALK inhibitors, leading to tumor recurrence or metastasis. The most critical issues that need to be addressed in the current treatment of ALK-positive NSCLC include the high cost of targeted inhibitors and the potential for increased toxicity and resistance to combination therapy. Recently, it has been suggested that the serine/threonine kinase 11 (STK11) mutation may serve as one of the biomarkers for immunotherapy in NSCLC. Therefore, the main purpose of this review was to summarize the role of STK11 in ALK-positive NSCLC. The present review also summarizes the treatment and drug resistance studies in ALK-positive NSCLC and the current status of STK11 research in NSCLC.

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