Non-small Cell Lung Cancer Research Articles

Nitric oxide facilitates the S-nitrosylation and deubiquitination of Notch1 protein to maintain cancer stem cells in human NSCLC.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality, with tumour heterogeneity, fueled by cancer stem cells (CSCs), intricately linked to treatment resistance. Therefore, it is imperative to advance therapeutic strategies targeting CSCs in NSCLC. In this study, we utilized RNA sequencing to investigate metabolic pathway alterations in NSCLC CSCs and identified a crucial role of nitric oxide (NO) metabolism in governing CSC stemness, primarily through modulation of the Notch1 protein. Mechanistically, NO-induced S-nitrosylation of Notch1 facilitated its interaction with the deubiquitylase UCHL1, leading to increased Notch1 protein stability and enhanced CSC stemness. By inhibiting NO synthesis and downregulating UCHL1 expression, we validated the impact of NO on the Notch signalling pathway and CSC stemness. Importantly, targeting NO effectively reduced CSC populations within patient-derived organoids (PDOs) during radiotherapy. This mechanism presents a promising therapeutic target to surmount radiotherapy resistance in NSCLC treatment.

Can Artificial Intelligence Help Us in the Evaluation of Coronary Artery Calcification Scores by Acting as a Prognosticator in Patients That Are Operated on Due to Non-Small Cell Lung Cancer? A Pivotal Study.

Background: Non-small cell lung cancer (NSCLC) is the leading cause of death from malignancies, and surgical resection is the most effective form of treatment. Coronary artery disease (CAD) is a common comorbidity in patients with NSCLC. A coronary artery calcium (CAC) score correlates with the extent of CAD. We aimed to test whether an automated assessment of CAC scores helps to identify the population of patients with a higher risk of postoperative complications and worse overall survival (OS) after the surgical treatment of NSCLC. Methods: In this retrospective cohort study, the data of the patients who were surgically treated for NSCLC were matched with the reassessed preoperative CT images. The postoperative complication rates and overall survival were analyzed. The CAC score was evaluated automatically using the Syngo.via Siemens Healthcare software. Cardiac age was assessed according to Hoff et al. 2001. The prognosticators of postoperative complications and of OS were tested. Results: The data of 193 patients with complete data, an adherence to the inclusion and exclusion criteria, and that were operated between 2018 and 2019, were included. Cardiac age was a predictor of the cardiovascular and pulmonary complications rate (95%CI -0.007-0.203, p = 0.066, beta coefficient 0.098). In a multivariable stepwise regression analysis, operative access was a predictor of cardiovascular and pulmonary complications (95%CI -0.290--0.111, p < 0.001, beta coefficient -0.200), cardiovascular complications (95%CI -0.161--0.022, p = 0.011, beta coefficient -0.036), and the general complication rate (95%CI -0.370--0.194, p < 0.001, beta coefficient -0.286). Kaplan-Meier curves were separated in the survival analysis of groups of patients with a cardiac age 0-69 years vs. an age of 70+ (92 vs. 92 patients) (in Cox regression analysis, HR = 1.678, 95%CI 0.847-3.292 p = 0.138). Conclusions: An automated CAC score assessment may be a potential and clinically meaningful prognosticator of both postoperative complications and OS in patients that are operated on due to NSCLC. Further studies are required.

Enhanced NSCLC subtyping and staging through attention-augmented multi-task deep learning: A novel diagnostic tool

ObjectivesThe objective of this study is to develop a novel multi-task learning approach with attention encoders for classifying histologic subtypes and clinical stages of non-small cell lung cancer (NSCLC), with superior performance compared to currently popular deep-learning models. Material and methodsData were collected from six publicly available datasets in The Cancer Imaging Archive (TCIA). Following the inclusion and exclusion criteria, a total of 4548 CT slices from 758 cases were allocated. We evaluated multiple multi-task learning models that integrate attention mechanisms to resolve challenges in NSCLC subtype classification and clinical staging. These models utilized convolution-based modules in their shared layers for feature extraction, while the task layers were dedicated to histological subtype classification and staging. Each branch sequentially processed features through convolution-based and attention-based modules prior to classification. ResultsOur study evaluated 758 NSCLC patients (mean age, 66.2 years ± 10.3; 473 men), spanning ADC and SCC cases. In the classification of histological subtypes and clinical staging of NSCLC, the MobileNet-based multi-task learning model enhanced with attention mechanisms (MN-MTL-A) demonstrated superior performance, achieving Area Under the Curve (AUC) scores of 0.963 (95 % CI: 0.943, 0.981) and 0.966 (95 % CI: 0.945, 0.982) for each task, respectively. The model significantly surpassed its counterparts lacking attention mechanisms and those configured for single-task learning, as evidenced by P-values of 0.01 or less for both tasks, according to DeLong’s test. ConclusionsThe integration of attention encoder blocks into our multi-task learning network significantly enhanced the accuracy of NSCLC histological subtyping and clinical staging. Given the reduced reliance on precise radiologist annotation, our proposed model shows promising potential for clinical application.

Neuronatin Promotes the Progression of Non-small Cell Lung Cancer by Activating the NF-κB Signaling.

Understanding the regulatory mechanisms involving neuronatin (NNAT) in non-small cell lung cancer (NSCLC) is an ongoing challenge. This study aimed to elucidate the impact of NNAT knockdown on NSCLC by employing both in vitro and in vivo approaches. To investigate the role of NNAT, its expression was silenced in NSCLC cell lines A549 and H226. Subsequently, various parameters, including cell proliferation, invasion, migration, and apoptosis, were assessed. Additionally, cell-derived xenograft models were established to evaluate the effect of NNAT knockdown on tumor growth. The expression of key molecules, including cyclin D1, B-cell leukemia/lymphoma 2 (Bcl-2), p65, matrix metalloproteinase (MMP) 2, and nerve growth factor (NGF) were examined both in vitro and in vivo. Nerve fiber density within tumor tissues was analyzed using silver staining. Upon NNAT knockdown, a remarkable reduction in NSCLC cell proliferation, invasion, and migration was observed, accompanied by elevated levels of apoptosis. Furthermore, the expression of cyclin D1, Bcl-2, MMP2, and phosphorylated p65 (p-p65) showed significant downregulation. In vivo, NNAT knockdown led to substantial inhibition of tumor growth and a concurrent decrease in cyclinD1, Bcl-2, MMP2, and p-p65 expression within tumor tissues. Importantly, NNAT knockdown also led to a decrease in nerve fiber density and downregulation of NGF expression within the xenograft tumor tissues. Collectively, these findings suggest that neuronatin plays a pivotal role in driving NSCLC progression, potentially through the activation of the nuclear factor-kappa B signaling cascade. Additionally, neuronatin may contribute to the modulation of tumor microenvironment innervation in NSCLC. Targeting neuronatin inhibition emerges as a promising strategy for potential anti-NSCLC therapeutic intervention.

Sinensetin inhibits the movement ability and tumor immune microenvironment of non-small cell lung cancer through the inactivation of AKT/β-catenin axis.

Although current treatment strategies have improved clinical outcomes of non-small cell lung cancer (NSCLC) patients, side effect and prognosis remain a hindrance. Thus, safer and more effective therapeutical drugs are needed for NSCLC. Sinensetin (Sin) is a flavonoid from citrus fruits, which exhibits antitumor effect on diverse cancers. However, the effect and mechanism of Sin on NSCLC remain unknown. In this study, NSCLC cell lines, and tumor-bearing mice were treated with Sin. The effect and mechanism of Sin were addressed using cell counting kit-8, transwell, enzyme-linked immunosorbent assay, hematoxylin and eosin, immunohistochemistry, and western blot analysis assays in both cell and animal models. Sin reduced the cell viability of A549 and H1299, with the IC50 of 81.46 µM and 93.15 µM, respectively. Sin decreased invaded cell numbers, the expression of N-cadherin and vascular endothelial growth factor A (VEGFA), while increased the E-cadherin level, the cytotoxicity of CD8+ T cells, and the concentration of interferon-γ (IFN-γ), interleukin-2 (IL-2), and tumor necrosis factor-α (TNF-α) in NSCLC cells. Mechanistically, Sin declined the expression of protein kinase B (AKT)/β-catenin pathway, which was restored with the application of SC79, an activator of AKT. The inhibitory role of Sin in NSCLC cell proliferation, invasion, epithelial-mesenchymal transition (EMT) and immune escape was reversed by the management of SC79. In vivo, Sin reduced tumor size and weight, and the expression of N-cadherin, VEGFA, and AKT/β-catenin pathway, but enhanced the level of E-cadherin and IFN-γ. Taken together, Sin suppressed cell growth, invasion, EMT and immune escape via AKT/β-catenin pathway in NSCLC.

Asiatic acid induces lung cancer toxicity by triggering SRC-mediated ferroptosis

Ferroptosis is a recently discovered form of regulated cell death that shows promise as a novel approach for inducing tumor cell death in cancer treatment, with significant research potential. Asiatic acid (AA), a key component of the traditional Chinese medicine Centella asiatica, has been identified as having potential therapeutic benefits for various diseases, particularly cancer. Non-small cell lung cancer (NSCLC) is a challenging and prevalent form of cancer to treat. In our study, we utilized network pharmacology, molecular docking, and experimental methods to investigate the potential of AA in treating NSCLC and to elucidate its role in inhibiting cancer through the ferroptosis pathway. Through network pharmacology analysis, we identified that AA targets the core NSCLC protein SRC through the ferroptosis pathway. Our experiments demonstrated that treatment with AA led to increased iron accumulation, mitochondrial membrane potential, and expression of ferroptosis markers glutathione peroxidase 4 (GPX4), ferritin heavy chain 1 (FTH1), and acyl-CoA synthetase long chain family member 4 (ACSL4) in NSCLC cells, confirming the induction of ferroptosis. In conclusion, AA has the potential to target SRC and induce NSCLC cell death through the ferroptosis pathway, offering a promising approach for cancer treatment.

Three-dimensional conformal radiation therapy with concurrent chemotherapy for stage III non-small cell lung cancer: protocol for a systematic review and meta-analysis

IntroductionLung cancer continues to be a common form of cancer worldwide and a primary contributor to cancer-related fatalities. Non-small cell lung cancer (NSCLC) is the most prevalent form, making up...

Dauricine Inhibits Non-small Cell Lung Cancer Development by Regulating PTEN/AKT/mTOR and Ras/MEK1/2/ERK1/2 Pathways in a FLT4-dependent Manner.

Non-small cell lung cancer (NSCLC) is still a solid tumor with high malignancy and poor prognosis. Vascular endothelial growth factor receptor 3 (FLT4, VEGFR3) is overexpressed in NSCLC cells, making it a potential target for NSCLC treatment. In this study, we aimed to explore the anti-cancer effects of dauricine on NSCLC cells and its mechanism targeting FLT4. We found that dauricine inhibited the growth of NCI-H1299 cells by blocking the cycle in the G2/M phase through flow cytometry analysis. In addition, dauricine also inhibited the migration of NCI-H1299 cells by wound healing assay and transwell migration assay. More importantly, our empirical analysis found the anti-cancer effect of dauricine on NCI-H1299 cells and the protein level of FLT4 had a distinctly positive correlation, and this effect was weakened after FLT4 knockdown. It is suggested that dauricine suppressed the growth and migration of NCI-H1299 cells by targeting FLT4. Furthermore, dauricine inhibited FLT4 downstream pathways, such as PTEN/AKT/mTOR and Ras/MEK1/2/ERK1/2, thereby regulating cell migration-related molecule MMP3 and cell cycle-related molecules (CDK1, pCDK1-T161, and cyclin B1). Dauricine may be a promising FLT4 inhibitor for the treatment of NSCLC.

How to Keep Up With Molecular Testing and Targeted Therapies in Lung Cancer.

Until the early 2000s, advanced or metastatic non-small cell lung cancer (NSCLC) was treated as a single disease with all histologic subtypes treated alike with standard chemotherapy agents. Over the past two decades, the treatment paradigms for advanced NSCLC have changed dramatically with the discovery of multiple targeted therapies that are now approved for the treatment of NSCLC tumors with specific oncogene drivers or molecular alterations. Molecular testing has become integrated and critical for the clinical management of advanced NSCLC. The discovery and success of these targeted therapies have reshaped the classification of NSCLC on the basis of molecular classification and enabled a personalized approach in thoracic oncology. In this review, we discuss recent developments in the molecular profiling of NSCLC, and approved and emerging targeted therapies for the treatment of NSCLC.

A subset of neutrophils activates anti-tumor immunity and inhibits non-small-cell lung cancer progression.

Neutrophils in the tumor microenvironment (TME) are heterogeneous populations associated with cancer prognosis and immunotherapy. However, the plasticity and function of heterogeneous neutrophils in the TME of non-small-cell lung cancer (NSCLC) remain unclear. Here, we show that neutrophils produce high levels of interleukin (IL)-8, which induce the differentiation of CD74highSiglecFlow neutrophils and suppress the generation of CD74lowSiglecFhigh neutrophils in the TME of IL-8-humanized NSCLC mice. The CD74highSiglecFlow neutrophils boost anti-tumor Tcell responses via antigen cross-presentation. Deleting CD74 in IL-8-humanized neutrophils impairs Tcell activation and exacerbates NSCLC progression, whereas a CD74 agonist enhances Tcell activation and the efficacy of anti-programmed cell death 1 (PD-1) or osimertinib therapies. Additionally, the CD74highCD63low neutrophils in the TME and peripheral blood of advanced NSCLC patients phenocopy the CD74highSiglecFlow neutrophils in the TME of NSCLC mice and correlate well with the responsiveness to anti-PD-1 plus chemotherapies. These findings demonstrate an IL-8-CD74high neutrophil axis that promotes anti-tumor immunity in NSCLC.

Combination Immunotherapy With Radiotherapy in Non-Small Cell Lung Cancer: A Review of Evidence.

Radiotherapy plays a fundamental role in the treatment of patients with all stages of non-small-cell lung cancer (NSCLC). The emergence of immune checkpoint inhibitors (ICIs) has transformed the standard of care in these patients. The use of ICIs is increasingly utilized in the definitive setting as an adjunct to chemoradiotherapy or surgery and remains a vital component in the treatment of metastatic disease. Despite improvements in patient survival, the use of immunotherapy as monotherapy has shown limited overall response rates with susceptibility to resistance. Radiotherapy has been identified as a viable option to enhance the response rate to ICI and improve outcomes in NSCLC. We queried the English PubMed database utilizing variably combined search items including "radiation," "chemoradiation," "immune checkpoint," "immunotherapy," "stereotactic body radiotherapy," and "non-small-cell lung". We additionally searched various acceptable alternative terms for similar keywords such as "radiotherapy" in place of "radiation." These results were subsequently curated for relevance and impact on current treatment paradigms. In this review, we discuss preclinical and clinical studies relating to combinatorial use of immunotherapy and radiation in NSCLC. These studies are presented in the context of early-stage, operable stage III, unresectable stage III, and metastatic disease. The majority of the data illustrate promising results regarding the additive or synergistic effects of radiation and immunotherapy with a suggestion that the timing of these treatment modalities is crucial to optimizing outcomes. While there is now evidence regarding the favorable interplay between radiation and immunotherapy in NSCLC, there remain multiple unanswered questions which are expected to be addressed in ongoing clinical trials.

Cost‐Effectiveness Analysis of Adjuvant Alectinib versus Platinum‐Based Chemotherapy in Resected ALK‐Positive Non‐Small‐Cell Lung Cancer in the Chinese Health Care System

ABSTRACTObjectivesThe ALINE trial demonstrated the superiority of alectinib over platinum‐based chemotherapy in resected Anaplastic Lymphoma Kinase (ALK)‐positive non‐small‐cell lung cancer (NSCLC). Considering the high cost of alectinib, this study aimed to evaluate the economic value of alectinib compared to platinum‐based chemotherapy for treating early‐stage ALK‐positive NSCLC from the perspective of the Chinese health care system.Materials and MethodsWe developed a five‐state Markov model with monthly cycles to estimate the lifetime costs, life‐years (LYs), quality‐adjusted life‐years (QALYs), and incremental cost‐effectiveness ratios (ICERs) in terms of cost per LY gained and per QALY gained. Costs were obtained from database, expert opinions and published literature, and utilities were primarily derived from a multicenter cross‐sectional study based on the Chinese population. Costs and outcomes were discounted at 5% per year. Sensitivity analyses and scenario analyses were conducted to assess uncertainty in model results.ResultsCompared to platinum‐based chemotherapy, alectinib increased total costs by $16,245 and provided gains of 2.02 LYs and 1.84 QALYs over a lifetime horizon. ICERs were $8,052/LY and $8,806/QALY. The ICER in terms of cost per QALY gained was most sensitive to the outcome discount rate. Probabilistic sensitivity analysis indicated a 93% probability of alectinib being cost‐effective at a willing‐to pay (WTP) threshold of $12,367/QALY (1 GDP per capita), rising to 100% at $37,100/QALY (3 GDP per capita).ConclusionAlectinib appears to be the preferred cost‐effective option in the adjuvant treatment for Chinese patients with resected early‐stage ALK‐positive NSCLC.

Impact of Bone Metastasis in Stage IV Non–Small Cell Lung Cancer Treated With Durvalumab and Tremelimumab With or Without Chemotherapy: A Retrospective Analysis of the CCTG BR.34 Trial

PURPOSE This retrospective analysis examines the impact of bone metastasis on outcomes in patients with non–small cell lung cancer (NSCLC) from the CCTG BR.34 trial, which investigated the combined immune checkpoint blockade. MATERIALS AND METHODS The CCTG BR.34 trial was a randomized phase II study assessing durvalumab plus tremelimumab, with or without platinum-doublet chemotherapy, in 301 patients with metastatic NSCLC. Patients were categorized into two cohorts on the basis of bone metastasis: cohort A (n = 129) and cohort B (n = 172). The primary end point was overall survival (OS), analyzed using Cox regression and multivariable models. RESULTS Patients with bone metastasis had notably poorer outcomes. The median OS was 10.9 months for those with bone metastasis versus 18.7 months for those without (hazard ratio [HR] 1.68, P = .001). The median progression-free survival (PFS) was 3.4 months with bone metastasis compared with 7.2 months without (HR, 1.82, P &lt; .0001). The overall response rate (ORR) was lower in patients with bone metastasis (29.5%) compared with those without (45.9%; odds ratio [OR], 0.52, P = .01). Adding chemotherapy to durvalumab plus tremelimumab did not significantly affect OS ( P = .23), PFS ( P = .84), or ORR ( P = .25) in relation to bone metastasis. Multivariable analysis reaffirmed that bone metastasis was linked to decreased OS (HR, 1.42, P = .036), PFS (HR, 1.69, P &lt; .0001), and ORR (OR, 0.52, P = .01). CONCLUSION Bone metastasis was associated with worse outcomes in this dual immune checkpoint blockade trial, with or without chemotherapy. Future trials should consider bone metastasis as a stratification factor and explore combining immune checkpoint inhibitors with targeted therapies addressing bone microenvironment factors (eg, interleukin-8, PTHrP, and transforming growth factor-β).

Pan-cancer analysis of IRF1 focusing on prognostic and immunological roles in non-small cell lung cancer

Interferon regulatory factor 1 (IRF1) significantly affects tumour occurrence and development. This study aimed to analyse its function as a pan-cancer prognostic indicator. We compared IRF1 expression and prognostic significance in normal and tumour samples from different databases. Accordingly, we performed in vitro experiments and immunohistochemistry (IHC) to investigate the role of IRF1 in non-small cell lung cancer (NSCLC). Our findings indicate that IRF1 expression is significantly correlated with prognosis, the tumour microenvironment, and immune cell infiltration. Furthermore, receiver operating characteristic (ROC) analysis revealed that IRF1 had high accuracy in distinguishing cancerous tissues from normal ones. Notably, IRF1 expression was linked to immune-related and immune checkpoint genes. Cell proliferation, invasion, and migration were significantly related to IRF1 expression. IHC indicated that IRF1 was downregulated in NSCLC tissues. Our study provides comprehensive bioinformatic analysis and experimental verification of IRF1, suggesting its potential as a prognostic biomarker in cancer.

Methylation modification is a poor prognostic factor in non-small cell lung Cancer and regulates the tumor microenvironment: mRNA molecular structure and function

Non-small cell lung cancer (NSCLC) is the most common and deadly type of lung cancer, and its poor prognosis is closely related to the complex interactions of the tumor microenvironment. Through methylation analysis of tumor tissue samples from NSCLC patients, combined with high-throughput sequencing technology, the methylation status and structural characteristics of mRNA molecules were studied. Bioinformatics tools were used to analyze the regulatory effects of methylation modification on mRNA expression and genes associated with the tumor microenvironment. The results showed that the methylation level of specific mRNA was significantly correlated with the expression changes of tumor microenvironment-related factors. In addition, methylation modification affected mRNA stability and translation efficiency, further altering the metabolic activity and immune escape capacity of tumor cells. The results showed that mRNA with high methylation level was significantly associated with poor prognosis. Methylation modification profoundly affects the tumor microenvironment and prognosis of non-small cell lung cancer by altering the structure and function of mRNA molecules.

[Artículo traducido] Adherencia al tratamiento con quimioterapia oral en pacientes con cáncer de pulmón no microcítico localmente avanzado o metastásico: protocolo para un estudio de vida real realizado en farmacia hospitalaria

ObjectiveThis article describes a study protocol for evaluating adherence to oral chemotherapy (OCT) in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) in Spain. MethodsThis multicenter, observational, prospective study will be conducted by six hospital pharmacists from six Spanish hospitals. The study will include men and women aged 18 years or older with a diagnosis of locally advanced or metastatic NSCLC who are being treated or have been prescribed OCT. Once included, the patient will be active and prospectively followed up for 3 months, including four study visits to record information on sociodemographic variables, antineoplastic treatment and adherence, pharmaceutical care, clinical variables, and patient-reported outcomes (PRO) (the 3-level version of EQ-5D, the EORTC Core Quality of Life Questionnaire, the Brief Illness Perception Questionnaire, the Treatment Satisfaction with Medicines Questionnaire, and the PRO version of Common Terminology Criteria for Adverse Events). Twelve months after patient inclusion, we will record information on the disease progression status and dispensed prescriptions. The primary outcome is the percentage of treatment adherence that will be calculated based on the pill count as follows: the difference between the number of pills dispensed minus the number of unused pills will be divided by the number of days of treatment multiplied by the number of pills/day prescribed by the oncologist; this quotient will be multiplied by 100 to obtain the percentage of adherence. Based on the that pill count reconciliation, those with a percentage adherence greater than80% will be primarily categorized as adherent. Secondarily, treatment adherence will be also calculated based on the proportion of days covered and the 4-items Morisky Green Levine Medication Adherence Scale. To analyze the impact of patients' and treatment characteristics on adherence, bivariate analyses will be performed using different adherence cut-off points. To evaluate the impact of adherence on treatment efficacy as evaluated by progression-free survival, we will be using the Kaplan–Meier method and compare it with the log-rank test and univariate Cox regression analysis. ConclusionsWe expect that our study will provide initial information on key aspects of adherence to OCT (measurement, facilitators, and barriers) and its relationship with patients' and clinically relevant outcomes in the setting of NSCLC, and that this information will help in designing pharmaceutical interventions to improve adherence.

In vitro effectiveness of CB469, a MET tyrosine kinase inhibitor in MET-activated cancer cells

Gene alterations in receptor tyrosine kinases can result in oncogenic driver mutation in non-small cell lung cancer (NSCLC) including in genes like EGFR, ALK and MET. MET amplifications and MET exon14 skipping are the primary genetic changes in MET-altered cancers. Acquired MET mutations mediate resistance to clinical MET-targeted therapy in NSCLC. MET kinase domain secondary mutations (D1228X, Y1230X) confer resistance to type I MET tyrosine kinase inhibitors (TKIs) in METexon14-altered or MET amplified NSCLC. Here, we investigated the preclinical activity of a novel MET inhibitor, CB469, with cell growth, signaling pathway and colony formation. We confirmed that CB469 inhibited the activity of MET wild and secondary mutant kinases, D1228N and Y1230H, as a type II inhibitor. CB469 also inhibited cell growth and cell signaling proteins in MET-activated or MET exon14 skipping-mutated cancer cell lines and NIH/3T3 cells expressing an engineered MET mutant. CB469 exhibited the inhibitory efficacy comparable with that of capmatinib in migration of EBC-1(METwt) and Hs746T(METΔex14) cells. Finally, CB469 showed selective and potent inhibition in MET-activated cancer cells among MET TKIs leading to enhanced selectivity for MET-mutant versus wild type MET with inhibition of cell growth in NIH/3T3 cells expressing an engineered MET mutant variant.

Patient-Initiated Nationwide Survey on Testing for Actionable Oncogenic Drivers in Non-Small Cell Lung Cancer in Japan.

Previous reports indicated still low implementation rates of multigene testing for advanced non-small cell lung cancer (NSCLC) in Japan. This is a retrospective study launched at the initiative of lung cancer patients. Patients with stage IV NSCLC from January 2019 to December 2022 were investigated for testing of 8 actionable oncogenic drivers with targeted therapies available as of 2022. A total of 15,719 patients were included. Between 2019 and 2022, the percentage of patients who were not tested for any actionable oncogenic drivers remained the same, ranging from 21.5% to 33.1%. However, since late 2021, the percentage of patients tested for five or more actionable oncogenic drivers has increased. Across hospital categories and regions, the number of actionable oncogenic drivers tested was similar. This patient-initiated national survey in Japan reveals the recent nationwide increase in testing rates for actionable oncogenic drivers in Advanced NSCLC.

E3 ubiquitin ligase DTX2 fosters ferroptosis resistance via suppressing NCOA4-mediated ferritinophagy in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) remains the foremost contributor to cancer-related fatalities globally, with limited effective therapeutic modalities. Recent research has shed light on the role of ferroptosis in various types of cancers, offering a potential avenue for improving cancer therapy. Herein, we identified E3 ubiquitin ligase deltex 2 (DTX2) as a potential therapeutic target candidate implicated in promoting NSCLC cell growth by inhibiting ferroptosis. Our investigation revealed a significant upregulation of DTX2 in NSCLC cells and tissues, which was correlated with poor prognosis. Downregulation of DTX2 suppressed NSCLC cell growth both in vitro and in vivo, while its overexpression accelerated cell proliferation. Moreover, knockdown of DTX2 promoted ferroptosis in NSCLC cells, which was mitigated by DTX2 overexpression. Mechanistically, we uncovered that DTX2 binds to nuclear receptor coactivator 4 (NCOA4), facilitating its ubiquitination and degradation via the K48 chain, which subsequently dampens NCOA4-driven ferritinophagy and ferroptosis in NSCLC cells. Notably, DTX2 knockdown promotes cisplatin-induced ferroptosis and overcomes drug resistance of NSCLC cells. These findings underscore the critical role of DTX2 in regulating ferroptosis and NCOA4-mediated ferritinophagy, suggesting its potential as a novel therapeutic target for NSCLC.

Association between Immune-Related Adverse Events and Atezolizumab in Previously Treated Patients with Unresectable Advanced or Recurrent Non-Small Cell Lung Cancer.

Real-world, large-scale studies on the association between immune-related adverse events (irAE) and immune checkpoint inhibitor therapy effectiveness are limited. We evaluated overall survival (OS) and progression-free survival based on the occurrence and grade of irAEs. We used data from Japanese patients with unresectable advanced or recurrent non-small cell lung cancer (NSCLC) who received atezolizumab and were enrolled in J-TAIL, a multicenter, prospective, single-arm observational study. Among the 1,002 patients, 190 (19.0%) developed irAEs. The most common irAEs were skin disorders (3.8%) of any grade and interstitial lung disease (1.5%) of grade ≥3. Patients who developed irAEs within 4 or 6 weeks of treatment initiation had higher baseline C-reactive protein levels than those without irAEs. OS was longer in patients with irAEs [HR, 0.66; 95% confidence interval (CI), 0.54-0.82], particularly in those with low-grade irAEs (HR, 0.45; 95% CI, 0.33-0.62), than in patients without irAEs. The HR (95% CI) for OS in patients with low-grade and high-grade skin or endocrine disorder-related irAEs was 0.42 (0.28-0.64) and 0.37 (0.15-0.88), respectively. The HR (95% CI) for OS in patients with low-grade and high-grade irAEs other than skin or endocrine disorders was 0.44 (0.30-0.65) and 1.27 (0.96-1.69), respectively. In patients with unresectable advanced or recurrent NSCLC treated with atezolizumab in real-world settings, irAEs are associated with a clinical benefit except in those with high-grade irAEs other than skin and endocrine disorders. Immune checkpoint inhibitors are useful for treating NSCLC but can cause life-threatening irAEs. This study had a large sample size and stratified the analysis by irAE type and grade. The results suggest that improved management of irAEs may improve the therapeutic effect of atezolizumab.