DNA methylation, an epigenetic modification, regulates gene transcription and maintains genome stability. DNA methyltransferase (DNMT) inhibitors can activate silenced genes at low doses and cause cytotoxicity at high doses. The ability of DNMT inhibitors to reverse epimutations is the basis of their use in novel strategies for cancer therapy. In this review, we examined the literature on DNA methyltransferase inhibitors. We summarized the mechanisms underlying combination therapy using DNMT inhibitors and clinical trials based on combining hypomethylation agents with other chemotherapeutic drugs. We also discussed the efficacy of such compounds as antitumor agents, the need to optimize treatment schedules and the regimens for maximal biologic effectiveness. Notably, the combination of DNMT inhibitors and chemotherapy and/or immune checkpoint inhibitors may provide helpful insights into the development of efficient therapeutic approaches.

Emotional distress (ED), commonly characterized by symptoms of depression and/or anxiety, is prevalent in patients with cancer. Preclinical studies suggest that ED can impair antitumor immune responses, but few clinical studies have explored its relationship with response to immune checkpoint inhibitors (ICIs). Here we report results from cohort 1 of the prospective observational STRESS-LUNG study, which investigated the association between ED and clinical efficacy of first-line treatment of ICIs in patients with advanced non-small-cell lung cancer. ED was assessed by Patient Health Questionnaire-9 and Generalized Anxiety Disorder 7-item scale. The study included 227 patients with 111 (48.9%) exhibiting ED who presented depression (Patient Health Questionnaire-9 score ≥5) and/or anxiety (Generalized Anxiety Disorder 7-item score ≥5) symptoms at baseline. On the primary endpoint analysis, patients with baseline ED exhibited a significantly shorter median progression-free survival compared with those without ED (7.9 months versus 15.5 months, hazard ratio 1.73, 95% confidence interval 1.23 to 2.43, P = 0.002). On the secondary endpoint analysis, ED was associated with lower objective response rate (46.8% versus 62.1%, odds ratio 0.54, P = 0.022), reduced 2-year overall survival rate of 46.5% versus 64.9% (hazard ratio for death 1.82, 95% confidence interval 1.12 to 2.97, P = 0.016) and detriments in quality of life. The exploratory analysis indicated that the ED group showed elevated blood cortisol levels, which was associated with adverse survival outcomes. This study suggests that there is an association between ED and worse clinical outcomes in patients with advanced non-small-cell lung cancer treated with ICIs, highlighting the potential significance of addressing ED in cancer management. ClinicalTrials.gov registration: NCT05477979.

Journal of Medical Internet Research - International Scientific Journal for Medical Research, Information and Communication on the Internet

Anaplastic lymphoma kinase (ALK) is a validated molecular target for non-small-cell lung cancer (NSCLC). The use of tyrosine kinase inhibitors (TKIs) has led to significantly improved survival benefits. However, the clinical benefits of targeting ALK using TKIs are limited due to the emergence of drug resistance. The landscape of resistance mechanisms and treatment decisions has become increasingly complex. Therefore, continued research into new drugs and combinatorial therapies is required to improve outcomes in NSCLC. In this review, we explore the resistance mechanisms of ALK TKIs in advanced NSCLC in order to provide a theoretical basis and research ideas for solving the problem of ALK drug resistance.

Chronic stress is common among cancer patients due to the psychological, operative, or pharmaceutical stressors at the time of diagnosis or during the treatment of cancers. The continuous activations of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS), as results of chronic stress, have been demonstrated to take part in several cancer-promoting processes, such as tumorigenesis, progression, metastasis, and multi-drug resistance, by altering the tumor microenvironment (TME). Stressed TME is generally characterized by the increased proportion of cancer-promoting cells and cytokines, the reduction and malfunction of immune-supportive cells and cytokines, augmented angiogenesis, enhanced epithelial-mesenchymal transition, and damaged extracellular matrix. For the negative effects that these alterations can cause in terms of the efficacies of anti-cancer treatments and prognosis of patients, supplementary pharmacological or psychotherapeutic strategies targeting HPA, SNS, or psychological stress may be effective in improving the prognosis of cancer patients. Here, we review the characteristics and mechanisms of TME alterations under chronic stress, their influences on anti-cancer therapies, and accessory interventions and therapies for stressed cancer patients.

Background: Diagnosing and treating patients with multiple primary lung cancers (MPLCs) bring challenges to the clinic, and the preliminary evidence has revealed unsatisfying outcomes after targeted therapy and immunotherapy. Therefore, we surveyed genomic profiles of MPLCs and their possible associations with tumor mutation burden (TMB), programmed death-ligand 1 (PD-L1), and the immune cell infiltration landscape. Materials and methods: A total of 112 patients with MPLCs with surgically resected 294 tumors were eligible, and 255 tumors were sequenced using a 1021-gene panel. Immunohistochemistry staining was performed to evaluate the levels of PD-L1 and the density of CD3+/CD8+ tumor-infiltrating lymphocytes (TILs), and CD68+/CD163+ tumor-associated macrophages (TAMs) at the central tumor and invasive margin, and immunotypes were generated based on those variables. Results: MPLCs often occur simultaneously in non-smoker women younger than 60 years and manifest as ground-glass opacities, adenocarcinoma, and stage I lung lesions. The most frequently mutated genes in the 255 tumors were EGFR (56%), ERBB2 (12%), TP53 (12%), BRAF (11%), RBM10 (11%), and KRAS (9%). We found 87 (77.7%) patients with diverse genomic profiles, and 61 (54.5%) who shared at least one putative driver gene between different tumors presented more aggressive tumors. The median TMB was 1.92 mutations/Mb, and high-TMB (≥3) lesions often harbored EGFR^L858R/KRAS^G12C/RBM10/TP53/LRP1B mutations or wild-type ERBB2. Only 8.1% of patients and 3.9% of lesions were positive for PD-L1 on tumor cells, and this positivity was more frequent in LRP1B/TP53-mutant tumors. EGFR^L858R/RBM10/TP53 mutations were positively associated with specific immune cells and an inflamed immunotype, but ERBB2 mutations were negatively correlated. TMB, CD3+TILs, and CD68+/CD163+ TAMs presented with significant heterogeneity among paired tumors (all kappa <0.2), but PD-L1 and CD8 +TILs were more uniformly present in tumor pairs. Conclusion: MPLCs are driven by different molecular events and often exhibit low TMB, low PD-L1, and a heterogeneous immune infiltration landscape. Specific genomic profiles are associated with TMB and the tumor immune microenvironmental landscape in MPLCs. Our findings can help to guide MPLCs diagnoses and to identify patient populations that may benefit from immunotherapy and targeted therapy.