The incidence and mortality of lung cancer rank top three of all cancers worldwide. Accounting for 85% of the total number of lung cancer, non-small cell lung cancer (NSCLC) is an important factor endangering human health. Recently, targeted therapies against driver mutations and epigenetic alterations have made encouraging advances that benefit NSCLC patients. Druggable driver mutations, which mainly occur in EGFR, KRAS, MET, HER2, ALK, ROS1, RET and BRAF, have been identified in more than a quarter of NSCLC patients. A series of highly selective mutant targeting inhibitors, such as EGFR tyrosine kinase inhibitors and KRAS inhibitors, have been well studied and applied in clinical treatments, which greatly promote the overall survival of NSCLC patients. However, drug resistance has become a major challenge for targeted treatment, and a variety of methods to overcome drug resistance are constantly being developed, including inhibitors against new mutants, combination therapy with other pathway inhibitors, etc. In addition, epigenetics-based therapy is emerging. Epigenetic regulators such as histone deacetylases and non-coding RNA play a crucial role in the development of cancer and drug resistance by affecting multiple signaling pathways. Epigenetics-based therapeutic strategies combined with targeted drugs show great clinical potential. Many agents targeting epigenetic changes are being investigated in preclinical studies, with some already under clinical trials. This article focuses on driver mutations and epigenetic alterations in association with relevant epidemiological data. We introduce the current status of targeted inhibitors and known drug resistance, review advances in major targeted therapies with recent data from preclinical and clinical trials, and discuss the possibility of combination therapy against driver mutations and epigenetic alterations in overcoming drug resistance.

Background: Histone demethylase UTX has been reported to participate in the occurrence and development of many cancers in tissue-specific manners. However, the role of UTX in non-small cell lung cancer (NSCLC) and exactly what regulates the expression of UTX remains unclear. Here, we analyzed the role of UTX in NSCLC in association with the widely recognized tumor driver epidermal growth factor receptor (EGFR). Methods: UTX levels in clinical samples were detected by immunohistochemistry staining, western blotting and real-time quantitative PCR. The expression of UTX in tumor tissue was correlated with the phosphorylation of EGFR. Cell proliferation and migration were evaluated by MTT and wound-healing assays. The impact of EGFR and its downstream pathways on UTX was explored with corresponding inhibitors, and examined by western blotting and real-time quantitative PCR. Results: In this study, we found that the expression of UTX in cancer tissues of patients with NSCLC was significantly higher than that in paracancerous tissues, and positively associated with EGFR phosphorylation levels. In addition, in NSCLC cell lines, UTX can promote proliferation and migration, while inhibition of its enzyme activity suppressed cell growth. Moreover, UTX expression was significantly upregulated when EGFR signaling pathway was activated, and vice versa when EGFR pathway was inhibited by tyrosine kinase inhibitor. Further mechanistic studies suggested that the activation of EGFR activated its downstream JAK/STAT3 signaling pathway and promoted STAT3 phosphorylation; the phosphorylated STAT3 transcriptionally promoted the levels of UTX. Conclusions: These results suggest an “EGFR-STAT3-UTX” axis that plays an oncogenic role in NSCLC.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the established first-line treatment for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations, but survival advantages in advanced-stage cases remain modest and show interpatient variability. This study seeks to delineate real-world survival outcomes in stage IV EGFR-mutant NSCLC patients undergoing treatment with EGFR-TKIs and to identify independent prognostic factors impacting overall survival (OS). The findings are expected to be a reference for clinicians in managing advanced lung cancer patients. Clinical characteristics from advanced EGFR-mutant NSCLC patients who received EGFR-TKIs were retrospectively analyzed to investigate the association between clinical factors and overall survival. The median OS was 40.60 months (95% confidence interval: 34.72–46.48 months), with expected 1-, 3-, and 5-year OS of 87.2%, 57.8%, and 34.0%, respectively. Patients exhibiting specific characteristics, such as being under 60 years old, having stage IVA disease, adenocarcinoma histology, no liver or brain metastases, negative for neuron-specific enolase (NSE), carcinoembryonic antigen (CEA), cytokeratin fragment 19 (CYFRA 21 − 1), progastrin-releasing peptide (ProGRP), and those who received chemotherapy and radiotherapy exhibited significantly longer survival times compared to patients with the opposite characteristics (being 60 years or older, having stage IVB or IVC disease, non-adenocarcinoma histology, presence of liver or brain metastases, positive for CEA, NSE, ProGRP, CYFRA 21 − 1, and not receiving chemotherapy or radiotherapy) (P < 0.05). Cox univariate and multivariate analyses identified pathological type, liver metastasis, brain metastasis, NSE, CYFRA 21 − 1, EGFR-TKIs type, radiotherapy, and chemotherapy as independent prognostic factors for patients with stage IV NSCLC treated with EGFR-TKIs. Pathological type, liver metastasis, brain metastasis, NSE, and CYFRA 21 − 1 were identified as independent risk factors for stage IV NSCLC patients treated with EGFR-TKIs, while chemotherapy and radiotherapy were determined to be independent protective factors. Taking icotinib or gefitinib, as opposed to osimertinib, was an independent risk factor for advanced NSCLC patients.