Strategy For Non-small Cell Lung Cancer Research Articles

Exploring the association of ADAM17 expression with survival in patients with non-small cell lung cancer.

The A disintegrin and metalloprotease (ADAM) family is involved in many vital cellular events, from proliferation to migration, and accumulated evidence suggests its increased expression in malignant tumors. In this study, we investigated ADAM17 expression in non-small cell lung cancer (NSCLC) and its relationship with clinicopathological factors and survival. Immunohistochemical staining of ADAM expression was performed in 108 patients with NSCLC and in 54 control cases with no known malignant diagnosis. Association between ADAM17 expression, clinicopathological factors, and survival were analyzed. The Kaplan-Meier method was used for survival analysis. ADAM17 was lowly expressed in 89 (82.4%) and highly expressed in 19 (17.6%) of the patients with NSCLC. In univariate analysis, high ADAM17 expression, lymphovascular invasion, stage, and treatment response significantly affected progression-free survival (PFS) and overall survival (OS) (p < 0.05). Multivariate analysis also showed that high ADAM17 expression, lymphovascular invasion, stage, and treatment response were important prognostic factors for PFS and OS (p < 0.05). Our study revealed that high ADAM17 expression significantly associated with OS and PFS in patients with NSCLC. ADAM17 may potentially be the area of a new targeted treatment strategy in NSCLC. Thus, routine evaluation of ADAM17 expression in patients with NSCLC may be a future consideration.

Identification and Application of Emerging Biomarkers in Treatment of Non-Small-Cell Lung Cancer: Systematic Review.

Non-small-cell lung cancer (NSCLC) comprises approximately 85% of all lung cancer cases, often diagnosed at advanced stages, which diminishes the effective treatment options and survival rates. This systematic review assesses the utility of emerging biomarkers-circulating tumor DNA (ctDNA), microRNAs (miRNAs), and the blood tumor mutational burden (bTMB)-enhanced by next-generation sequencing (NGS) to improve the diagnostic accuracy, prognostic evaluation, and treatment strategies in NSCLC. Analyzing data from 37 studies involving 10,332 patients from 2020 to 2024, the review highlights how biomarkers like ctDNA and PD-L1 expression critically inform the selection of personalized therapies, particularly beneficial in the advanced stages of NSCLC. These biomarkers are critical for prognostic assessments and in dynamically adapting treatment plans, where high PD-L1 expression and specific genetic mutations (e.g., ALK fusions, EGFR mutations) significantly guide the use of targeted therapies and immunotherapies. The findings recommend integrating these biomarkers into standardized clinical pathways to maximize their potential in enhancing the treatment precision, ultimately fostering significant advancements in oncology and improving patient outcomes and quality of life. This review substantiates the prognostic and predictive value of these biomarkers and emphasizes the need for ongoing innovation in biomarker research.

Successive next-generation sequencing strategy for optimal fusion gene detection in non-small-cell lung cancer in clinical practice

Metastatic non-small-cell lung cancer (NSCLC) displays various molecular alterations in the RAS-MAPK pathway. In particular, NSCLCs show high rates of targetable gene fusion in ALK, RET, ROS1, NRG1 and NTRK, or MET exon 14 skipping. Rapid and accurate detection of gene fusion in EGFR/KRAS/BRAF mutations is important for treatment selection especially for first-line indications. RNA-based next-generation sequencing (NGS) panels appear to be the most appropriate as all targets are multiplexed in a single run. While comprehensive NGS panels remain costly for daily practice, optimal sequencing strategies using targeted DNA/RNA panel approaches need to be validated. Here, we describe our lung cancer screening strategy using DNA and RNA targeted approaches in a real-life cohort of 589 NSCLC patients assessed for molecular testing. Gene fusions were analysed in 174 patients negative for oncogene driver mutations or ALK immunohistochemistry in a two-step strategy. Targetable alterations were identified in 28% of contributive samples. Non-smokers had a 63.7% probability to have a targetable alteration as compared to 21.5% for smokers. Overall survival was significantly higher (p=0.03) for patients who received a molecularly matched therapy. Our study shows the feasibility in routine testing of NSCLC DNA/RNA molecular screening for all samples in a cost- and time-controlled manner. The significant high fusion detection rate in patients with wild-type RAS-MAPK tumours highlights the importance of amending testing strategies in NSCLC.

Targeting MEK in non-small cell lung cancer

The mitogen-activated protein kinase (MAPK or MEK) pathway modulates tumor cell survival and proliferation in non-small cell lung cancer (NSCLC). Unlike RAS or EGFR, activating mutations in MEK are exceedingly rare in NSCLC. Instead, enhanced activation of the MEK pathway is often linked to increased signaling by upstream oncogenic driver mutations. Thus far, MEK inhibitor monotherapy has shown little promise. However, treatment strategies involving MEK inhibition in combination with other targeted therapies in other oncogene-driven NSCLC has proven to be encouraging. For example, MEK inhibition - when combined with BRAF inhibition, - has shown strong anti-tumor activity in BRAF V600 mutated NSCLC. In this review, recent data on MEK inhibitor strategies in NSCLC are summarized. Furthermore, ongoing early phase trials investigating MEK inhibitor combination therapy with immunotherapy, chemotherapy and other oncogene drivers are highlighted. These and other studies could help inform future rational combination strategies of MEK-ERK inhibition in oncogene-driven NSCLC.

Evaluation of Mitochondrial Phagy (Mitophagy) in Human Non-small Adenocarcinoma Tumor Cells.

Non-small cell lung cancer (NSCLC) is a predominant form of lung cancer characterized by its aggressive nature and high mortality rate, primarily due to late-stage diagnosis and metastatic spread. Recent studies underscore the pivotal role of mitophagy, a selective form of autophagy targeting damaged or superfluous mitochondria, in cancer biology, including NSCLC. Mitophagy regulation may influence cancer cell survival, proliferation, and metastasis by modulating mitochondrial quality and cellular energy homeostasis. Herein, we present a comprehensive methodology developed in our laboratory for the evaluation of mitophagy in NSCLC tumor cells. Utilizing a combination of immunoblotting, immunocytochemistry, and fluorescent microscopy, we detail the steps to quantify early and late mitophagy markers and mitochondrial dynamics. Our findings highlight the potential of targeting mitophagy pathways as a novel therapeutic strategy in NSCLC, offering insights into the complex interplay between mitochondrial dysfunction and tumor progression. This study not only sheds light on the significance of mitophagy in NSCLC but also establishes a foundational approach for its investigation, paving way for future research in this critical area of cancer biology.

Glucose restriction induces AMPK-SIRT1-mediated circadian clock gene Per expression and delays NSCLC progression

The rhythmic expression of the circadian clock is intimately linked to the health status of the body. Disturbed circadian clock rhythms might lead to a wide range of metabolic diseases and even cancers. Our previous study showed that glucose restriction was able to inhibit non-small cell lung cancer (NSCLC). In the current study, we found that glucose restriction enhanced apoptosis and cell growth delay in NSCLC cells. In addition, we used GEPIA database analysis to derive different effects of each circadian clock gene on lung cancer tissue. Among these circadian clock genes, Per (Period) is lowly expressed in cancer tissues and highly expressed in normal tissues. Moreover, the higher expression of Per in cancer patients has a better prognostic significance. Furthermore, we revealed that glucose restriction induced the expression of the circadian clock gene Per in NSCLC cells by upregulating SIRT1 (Sirtuin1) via activation of the energy response factor AMPK (AMP-activated protein kinase). Changes in Per expression following upregulation or downregulation of AMPK were consistent with AMPK expression. Additionally, a low-carbohydrate ketogenic diet significantly delayed tumor progression in a xenograft tumor model of severe combined immunodeficiency (SCID) mice. Meanwhile, the ketogenic diet increased the expression of AMPK, SIRT1 and Per in vivo. Besides, the ketogenic diet was found to restore the normal rhythmic level of Per by Zeitgeber Time (ZT) experiments. Taken these together, these results indicated a novel mechanism that glucose restriction induces AMPK-SIRT1 mediated circadian clock gene Per expression and delays NSCLC progression, which provided more evidence for glucose restriction as an adjuvant clinical therapeutic strategy in NSCLC.

Integrative bioinformatics approaches to establish potential prognostic immune-related genes signature and drugs in the non-small cell lung cancer microenvironment.

Introduction: Research has revealed that the tumor microenvironment (TME) is associated with the progression of malignancy. The combination of meaningful prognostic biomarkers related to the TME is expected to be a reliable direction for improving the diagnosis and treatment of non-small cell lung cancer (NSCLC). Method and Result: Therefore, to better understand the connection between the TME and survival outcomes of NSCLC, we used the "DESeq2" R package to mine the differentially expressed genes (DEGs) of two groups of NSCLC samples according to the optimal cutoff value of the immune score through the ESTIMATE algorithm. A total of 978 up-DEGs and 828 down-DEGs were eventually identified. A fifteen-gene prognostic signature was established via LASSO and Cox regression analysis and further divided the patients into two risk sets. The survival outcome of high-risk patients was significantly worse than that of low-risk patients in both the TCGA and two external validation sets (p-value < 0.05). The gene signature showed high predictive accuracy in TCGA (1-year area under the time-dependent ROC curve (AUC) = 0.722, 2-year AUC = 0.708, 3-year AUC = 0.686). The nomogram comprised of the risk score and related clinicopathological information was constructed, and calibration plots and ROC curves were applied, KEGG and GSEA analyses showed that the epithelial-mesenchymal transition (EMT) pathway, E2F target pathway and immune-associated pathway were mainly involved in the high-risk group. Further somatic mutation and immune analyses were conducted to compare the differences between the two groups. Drug sensitivity provides a potential treatment basis for clinical treatment. Finally, EREG and ADH1C were selected as the key prognostic genes of the two overlapping results from PPI and multiple Cox analyses. They were verified by comparing the mRNA expression in cell lines and protein expression in the HPA database, and clinical validation further confirmed the effectiveness of key genes. Conclusion: In conclusion, we obtained an immune-related fifteen-gene prognostic signature and potential mechanism and sensitive drugs underling the prognosis model, which may provide accurate prognosis prediction and available strategies for NSCLC.

Assessing Access to And Outcomes of Medical Oncology and Radiation Oncology Consultation in Non-Small Cell Lung Cancer Patients: A Population-Based Study Using Administrative Data

Background: Therapeutic advances in non-small cell lung cancer (NSCLC) have shifted treatment away from chemotherapy towards immunotherapy, monoclonal antibody, and tyrosine kinase inhibitor therapy. Most studies focusing on access to specialist care and lung cancer treatment were conducted before novel therapeutic strategies in NSCLC. This study aimed to better understand and inform referral practices for patients with NSCLC in Ontario. Methods: A retrospective population-based study using linked administrative healthcare data was conducted between 2010 and 2019. The study cohort was defined as patients, aged 18 years of age or older, with a stage I to IV NSCLC diagnosis in Ontario. Primary outcome: medical oncology or radiation oncology consultation within 120 days of diagnosis. Prognostic factors for consultation and receipt of treatment were identified using logistic regression. Results: 73,849 patients were diagnosed with NSCLC with 61.3% and 50.9% receiving a medical oncology or radiation oncology consultation respectively. The median time to consultation was 24 days (interquartile range [IQR] 13-49 days). As the stage increased, consultation was more likely (odds ratio [OR] 6.07, 95% CI 5.78-6.38). As the distance to the nearest cancer center increased consultation was less likely (OR 0.72, 95% CI 0.67-0.78). Stage III NSCLC and patients aged 40-44 years were more likely to receive treatment OR 4.09 (95%CI 3.82-4.38) and OR 3.28 (95% CI 2.51-4.28) respectively. Conclusion: Even in a universal health care system, socioeconomic factors impact a patient’s access to specialist care. Given newer, more effective therapeutic options for NSCLC, access to specialist care must be equitable.

Triple blockade of Ido-1, PD-L1 and MEK as a potential therapeutic strategy in NSCLC

BackgroundDespite the recent progress in the treatment and outcome of Non Small Cell Lung Cancer (NSCLC), immunotherapy has still significant limitations reporting a significant proportion of patients not benefiting from therapy, even in patients with high PD-L1 expression. We have previously demonstrated that the combined inhibition of MEK and PD-L1 in NSCLC patients derived three dimensional cultures exerted significant synergistic effect in terms of immune-dependent cancer cell death. However, subsequent experiments analyzing the expression of Indoleamine 2,3-dioxygenase-1 (Ido-1) gene expression demonstrated that Ido-1 resulted unaffected by the MEK inhibition and even increased after the combined inhibition of MEK and PD-L1 thus representing a potential escape mechanism to this combination.MethodsWe analyzed transcriptomic profile of NSCLC lung adenocarcinoma cohort of TCGA (The Cancer Genome Atlas), stratifying tumors based on EMT (Epithelial mesenchymal Transition) score; in parallel, we investigated the activation of Ido-1 pathway and modulation of immune cytokines productions both in NSCLC cells lines, in peripheral blood mononuclear cells (PBMCs) and in ex-vivo NSCLC spheroids induced by triple inhibition with an anti-PD-L1 monoclonal antibody, the MEK inhibitor and the Ido-1 inhibitor.ResultsIn NSCLC lung adenocarcinoma patient cohort (from TCGA) Ido-1 gene expression was significantly higher in samples classified as mesenchymal according EMT score. Similarly, on a selected panel of NSCLC cell lines higher expression of MEK and Ido-1 related genes was detected in cells with mesenchymal phenotype according EMT score, thus suggesting a potential correlation of co-activation of these two pathways in the context of EMT, with cancer cells sustaining an immune-suppressive microenvironment. While exerting an antitumor activity, the dual blockade of MEK and PD-L1 enhances the secretion of pro-inflammatory cytokines (IFNγ, TNFα, IL-12 and IL-6) and, consequently, the expression of new immune checkpoints such as Ido-1. The triple inhibition with an anti-PD-L1 monoclonal antibody, the MEK inhibitor and the Ido-1 inhibitor demonstrated significant antiproliferative and proapoptotic activity on ex-vivo NSCLC samples; at the same time the triple combination kept increased the levels of pro-inflammatory cytokines produced by both PBMCs and tumor spheroids in order to sustain the immune response and simultaneously decreased the expression of other checkpoint (such as CTLA-4, Ido-1 and TIM-3) thus promoting an immune-reactive and inflamed micro-environment.ConclusionsWe show that Ido-1 activation is a possible escape mechanism to immune-mediated cell death induced by combination of PD-L1 and MEK inhibitors: also, we show that triple combination of anti-PD-L1, anti-MEK and anti-Ido-1 drugs may overcome this negative feedback and restore anti-tumor immune response in NSCLC patients’ derived three dimensional cultures.

EP04.01-018 Medical Oncology and Radiation Oncology Consultation in Non-small Cell Lung Cancer (NSCLC). A Population-Based Study Using Administrative Data

Therapeutic advances in non-small cell lung cancer (NSCLC) have shifted treatment away from chemotherapy towards immunotherapy (IO), monoclonal antibody and tyrosine kinase inhibitor (TKI) therapy. Most studies focusing on access to specialist care and lung cancer treatment were conducted before novel therapeutic strategies in NSCLC. This study aimed to better understand and inform referral practices for patients with NSCLC in Ontario.

Cancer-associated fibroblasts strengthen cell proliferation and EGFR TKIs resistance through aryl hydrocarbon receptor dependent signals in non-small cell lung cancer

The tumor microenvironment is a dynamic cellular milieu that interacts with cancer cells and promotes tumor progression and metastasis. However, the specific mechanisms by which the tumor microenvironment impacts cancer cells’ behaviors remain poorly understood. In this study, enriched cancer-associated fibroblasts (CAFs) were observed in tumor tissues isolated from epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) resistant non-small cell lung cancer (NSCLC) patients. CAFs isolated from tumor tissues were capable of producing tryptophan metabolite kynurenine (Kyn), which significantly increased the proliferation and EGFR TKIs resistance of NSCLC cells. In this study, it was further observed that the activation of tryptophan 2,3-dioxygenase (TDO) in CAFs, resulted in the enhanced capability of tryptophan metabolism in them compared to normal fibroblasts. As a result, Kyn produced by CAFs facilitated the up-regulation of Aryl Hydrocarbon Receptor (AhR) signals in NSCLC, thereby resulting in the downstream ATK and ERK signaling pathways activation. Finally, inhibition of AhR signals efficiently prevented tumor growth and development of EGFR TKIs resistance, eventually improved the outcome of EGFR TKIs, and described a promising therapeutic strategy for NSCLC.

Gankyrin modulated non-small cell lung cancer progression via glycolysis metabolism in a YAP1-dependent manner

Non-small cell lung cancer (NSCLC) is highly malignant and heterogeneous form of lung cancer and involves various oncogene alterations. Glycolysis, an important step in tumor metabolism, is closely related to cancer progression. In this study, we investigated the biological function and mechanism of action of Gankyrin in glycolysis and its association with NSCLC. Analyzed of data from The Cancer Genome Atlas as well as NSCLC specimens and adjacent tissues demonstrated that Gankyrin expression was upregulated in NSCLC tissues compared to adjacent normal tissues. Gankyrin was found to significantly aggravate cancer-related phenotypes, including cell viability, migration, invasion, and epithelial mesenchymal transition (EMT), whereas Gankyrin silencing alleviated the malignant phenotype of NSCLC cells. Our results reveal that Gankyrin exerted its function by regulating YAP1 expression and increasing its nuclear translocation. Importantly, YAP1 actuates glycolysis, which involves glucose uptake, lactic acid production, and ATP generation and thus might contribute to the tumorigenic effect of Gankyrin. Furthermore, the Gankyrin-accelerated glycolysis in NSCLC cells was reversed by YAP1 deficiency. Gankyrin knockdown reduced A549 cell tumorigenesis and EMT and decreased YAP1 expression in a subcutaneous xenograft nude mouse model. In conclusion, both Gankyrin and YAP1 play important roles in tumor metabolism, and Gankyrin-targeted inhibition may be a potential anti-cancer therapeutic strategy for NSCLC.

Identification of Prognostic Gene Biomarkers in Non-Small Cell Lung Cancer Progression by Integrated Bioinformatics Analysis.

Simple SummaryNon-small cell lung cancer (NSCLC) is a major contributor to cancer related deaths worldwide. The progression of NSCLC is linked to epithelial-mesenchymal transition (EMT), a biologic process that enables tumor cells to acquire an invasive phenotype and resistance to therapies. Discovery of novel biomarkers in NSCLC progression is essential for improved prognosis and pharmacological interventions. We performed an integrated bioinformatics analysis on available gene expression datasets of transforming growth factor β (TGF-β) induced EMT in NSCLC cell lines aiming to establish new prognostic biomarkers in the disease. The retrieved candidate genes were involved in protein modifications, regulation of cell death and cell adhesions, oxidation-reduction reactions of aerobic respiration and mitochondrial translation. Out of these genes, we identified ten prognostic gene biomarkers, mostly involved in protein modifications, whose expressions correlated with patient survival in NSCLC. This ten-gene prognostic signature will be useful to improve risk prediction and guide treatment strategies in NSCLC. Deciphering the exact functions of the biomarker genes previously not linked with NSCLC will also lead to a better understanding of the pathomechanism of NSCLC progression, revealing novel therapeutic targets in the disease.The progression of non-small cell lung cancer (NSCLC) is linked to epithelial-mesenchymal transition (EMT), a biologic process that enables tumor cells to acquire a migratory phenotype and resistance to chemo- and immunotherapies. Discovery of novel biomarkers in NSCLC progression is essential for improved prognosis and pharmacological interventions. In the current study, we performed an integrated bioinformatics analysis on gene expression datasets of TGF-β-induced EMT in NSCLC cells to identify novel gene biomarkers and elucidate their regulation in NSCLC progression. The gene expression datasets were extracted from the NCBI Gene Expression Omnibus repository, and differentially expressed genes (DEGs) between TGF-β-treated and untreated NSCLC cells were retrieved. A protein-protein interaction network was constructed and hub genes were identified. Functional and pathway enrichment analyses were conducted on module DEGs, and a correlation between the expression levels of module genes and survival of NSCLC patients was evaluated. Prediction of interactions of the biomarker genes with transcription factors and miRNAs was also carried out. We described four protein clusters in which DEGs were associated with ubiquitination (Module 1), regulation of cell death and cell adhesions (Module 2), oxidation-reduction reactions of aerobic respiration (Module 3) and mitochondrial translation (Module 4). From the module genes, we identified ten prognostic gene biomarkers in NSCLC. Low expression levels of KCTD6, KBTBD7, LMO7, SPSB2, RNF19A, FOXA2, DHTKD1, CDH1 and PDHB and high expression level of KLHL25 were associated with reduced overall survival of NSCLC patients. Most of these biomarker genes were involved in protein ubiquitination. The regulatory network of the gene biomarkers revealed their interaction with tumor suppressor miRNAs and transcription factors involved in the mechanisms of cancer progression. This ten-gene prognostic signature can be useful to improve risk prediction and therapeutic strategies in NSCLC. Our analysis also highlights the importance of deregulation of ubiquitination in EMT-associated NSCLC progression.

Histone Modification in NSCLC: Molecular Mechanisms and Therapeutic Targets.

Lung cancer is the leading cause of cancer mortality in both genders, with non-small cell lung cancer (NSCLC) accounting for about 85% of all lung cancers. At the time of diagnosis, the tumour is usually locally advanced or metastatic, shaping a poor disease outcome. NSCLC includes adenocarcinoma, squamous cell carcinoma, and large cell lung carcinoma. Searching for novel therapeutic targets is mandated due to the modest effect of platinum-based therapy as well as the targeted therapies developed in the last decade. The latter is mainly due to the lack of mutation detection in around half of all NSCLC cases. New therapeutic modalities are also required to enhance the effect of immunotherapy in NSCLC. Identifying the molecular signature of NSCLC subtypes, including genetics and epigenetic variation, is crucial for selecting the appropriate therapy or combination of therapies. Epigenetic dysregulation has a key role in the tumourigenicity, tumour heterogeneity, and tumour resistance to conventional anti-cancer therapy. Epigenomic modulation is a potential therapeutic strategy in NSCLC that was suggested a long time ago and recently starting to attract further attention. Histone acetylation and deacetylation are the most frequently studied patterns of epigenetic modification. Several histone deacetylase (HDAC) inhibitors (HDIs), such as vorinostat and panobinostat, have shown promise in preclinical and clinical investigations on NSCLC. However, further research on HDIs in NSCLC is needed to assess their anti-tumour impact. Another modification, histone methylation, is one of the most well recognized patterns of histone modification. It can either promote or inhibit transcription at different gene loci, thus playing a rather complex role in lung cancer. Some histone methylation modifiers have demonstrated altered activities, suggesting their oncogenic or tumour-suppressive roles. In this review, patterns of histone modifications in NSCLC will be discussed, focusing on the molecular mechanisms of epigenetic modifications in tumour progression and metastasis, as well as in developing drug resistance. Then, we will explore the therapeutic targets emerging from studying the NSCLC epigenome, referring to the completed and ongoing clinical trials on those medications.

Real-World Data for Integration Strategy of Radiotherapy (RT) With Immunotherapy in Metastatic Non-Small Cell Lung Cancer (NSCLC)

<h3>Purpose/Objective(s)</h3> Immune checkpoint inhibitors (ICIs) have proven effective in metastatic NSCLC. RT has been used for symptom palliation or aggressive consolidation with improvement of survival in this group of patients. The question of when and how to combine RT with ICIs needs to be further defined in this combination therapeutic strategy in NSCLC. The growing body of evidence demonstrated that RT-ICIs sequence, dose of RT and location of RT are matter to the treatment outcome. We retrospectively analyzed our institutional data as real-world data to further illustrate the role of RT in combination with ICIs for metastatic NSCLC. <h3>Materials/Methods</h3> We retrospectively studied patients from a single institution diagnosed with metastatic NSCLC who were treated with RT-ICIs. The impact of overall survival (OS) from patients' characteristic, histology of tumor, PD-L1 expression, RT BED₁₀ (biological equivalent dose) dose, number of site of RT, RT to bone/no-bone metastasis site, and sequence of RT-ICIs as well as neutrophil-lymphocyte ratio (NLR) before and after RT were analyzed using Kaplan-Meier methods. Cox proportional hazard regression analysis was performed to identify independent predictors for OS. <h3>Results</h3> A total of 80 patients received ICI+RT were enrolled into the study with a median follow-up of 15 months. Median OS 18.8 was months. Univariable analysis revealed that positive OS predictors (<i>P</i> < 0.05) were lower post-RT NLR, sequential RT-ICIs, higher BED₁₀ dose of RT, one site of RT and RT to no-bone metastasis site. The post-RT NLR, and BED₁₀ dose of RT were independent predictors for OS on multivariable Cox proportional hazard regression analysis. Kaplan-Meier estimates median OS of low/high post-RT NLR, sequential/concurrent RT-ICIs, higher/lower BED₁₀ dose of RT, one/a number of RT sites and RT to no bone/bone metastasis sites were 23.7/11.5 mo., 24.5/16.4 mo., 20.6/16.8 mo. and 21.8/16.6 mo., respectively. The histology of tumor, PD-L1 expression and whether received chemotherapy or not did not significantly impact on OS. <h3>Conclusion</h3> Our real-world data supports that synergistic effective of RT can be achieved in combination with ICIs for metastatic NSCLC when RT was admitted with sequential fashion, ablative dose to one and non-bone metastatic site. Together with significant prognostic value of Post-RT NLR, it has been clearly demonstrated that the integration strategy of RT with ICIs should choose RT which would not compromise existing innate immunity of patients.

Study Design and Rationale for Espera Trial: A Multicentre, Randomized, Phase II Clinical Trial Evaluating the Potential Efficacy of Adding SBRT to Pembrolizumab-Pemetrexed Maintenance in Responsive or Stable Advanced Non-Squamous NSCLC After Chemo-Immunotherapy Induction

BackgroundImprovement in radiotherapy techniques and expected outcomes, as well as in understanding the underlying biological mechanisms contributing to its action (immunomodulation in primis), led to the integration of this therapeutical approach in the current management of advanced non-small cell lung cancer (NSCLC), not only in oncogene-driven tumors, but also in non-oncogene addicted NSCLC where the combination of platinum-based chemotherapy plus pembrolizumab represents nowadays the pivotal strategy. In this light, we have designed a randomized phase II (ESPERa) trial to evaluate the efficacy and safety of adding Stereotactic Body Radiotherapy (SBRT) to pembrolizumab-pemetrexed maintenance in advanced NSCLC patients experiencing disease response or stability after chemo-immunotherapy induction. Patients and MethodsAdvanced non-oncogene addicted NSCLC patients with ECOG performance status of 0 or 1, who obtained disease response or stability after 4 cycles of platinum-based chemotherapy plus pembrolizumab will be randomized 2:1 to receive pembrolizumab-pemetrexed maintenance plus SBRT vs pembrolizumab-pemetrexed alone. The primary endpoint is progression-free survival (PFS). Concomitant translational researches will be performed to identify potential prognostic and/or predictive biomarkers, as well as to analyze and monitor tumour microenvironment and tumor-host interactions. ConclusionsAlthough available data suggest the safety and efficacy of combining immunotherapy and radiotherapy, their systematic integration in the current first-line landscape still remains to be explored. If the pre-planned endpoints of the ESPERa trial will be achieved, the addition of SBRT to pembrolizumab-pemetrexed maintenance as a strategy to consolidate and ideally improve the awaited benefit could be considered as a promising strategy in NSCLC undergoing first-line therapy, as well as an interesting approach to be evaluated in other disease setting, as well as in other oncological malignancies where immunotherapy represents nowadays the standard-of-care.

Silencing ZIC2 abrogates tumorigenesis and anoikis resistance of non-small cell lung cancer cells by inhibiting Src/FAK signaling

Aberrant expression of the zinc finger protein (ZIC) family has been extensively reported to contribute to progression and metastasis in multiple human cancers. However, the functional roles and underlying mechanisms of ZIC2 in non-small cell lung cancer (NSCLC) are largely unknown. In this study, ZIC2 expression was evaluated using qRT-PCR, western blot, and immunohistochemistry, respectively. Animal experiments in vivo and functional assays in vitro were performed to investigate the role of ZIC2 in NSCLC. Luciferase assays and chromatin immunoprecipitation (ChIP) were carried out to explore the underlying target involved in the roles of ZIC2 in NSCLC. Here, we reported that ZIC2 was upregulated in NSCLC tissues, and high expression of ZIC2 predicted worse overall and progression-free survival of NSCLC patients. Silencing ZIC2 repressed tumorigenesis and reduced the anoikis resistance of NSCLC cells. Mechanical investigation further revealed that silencing ZIC2 transcriptionally inhibited Src expression and inactivated steroid receptor coactivator/focal adhesion kinase signaling, which further attenuated the anoikis resistance of NSCLC cells. Importantly, our results showed that the number of circulating tumor cells (CTCs) was positively correlated with ZIC2 expression in NSCLC patients. Collectively, our findings unravel a novel mechanism implicating ZIC2 in NSCLC, which will facilitate the development of anti-tumor strategies in NSCLC.

Driver Gene Mutations and Risk of Lymph Node Metastasis in Non-Small Cell Lung Cancer

Non-Small Cell Lung Cancer (NSCLC) lymph node status is closely related to its diagnosis, treatment, and prognosis. The lymph node status is an important basis for formulating clinical treatment strategies of NSCLC, therefore comprehensive and profound understanding of risk factors for lymph node metastasis is essential. There are many known factors for lymph node metastasis in NSCLC, such as pathological subtypes, tumor size, tumor location. Meanwhile, whether the mutation of the driver gene affects the lymph node metastasis is still lacking enough research. This article aims to elaborate the relationship between NSCLC driver gene mutation and lymph node metastasis, from NSCLC lymph node metastasis-related risk factors, driver genes and lymph node metastasis, metastatic lymph node mutation status analysis and detection these several aspects to summarize the latest research progress in NSCLC driver gene mutation and lymph node metastasis risk. It also fully explained the correlation between driver gene mutations and NSCLC tumor biological behaviors such as lymph node metastasis.

CKAP2L Promotes Non-Small Cell Lung Cancer Progression through Regulation of Transcription Elongation.

Chromosomal instability (CIN) is a driver of clonal diversification and intratumor heterogeneity, providing genetic diversity that contributes to tumor progression. It is estimated that approximately 80% of solid cancers, including non-small cell lung cancer (NSCLC), exhibit features of CIN, which affects tumor growth and response to therapy. However, the molecular mechanisms connecting CIN to tumor progression are still poorly understood. Through an RNAi screen performed on genes involved in CIN and overexpressed in human lung adenocarcinoma samples, we identified the cytoskeleton-associated protein 2-like (CKAP2L) as a potential oncogene that promotes lung cancer proliferation and growth in vitro and in vivo. Mechanistically, CKAP2L directly interacted with RNA Pol II and regulated transcription elongation of key genes involved in spindle assembly checkpoint, chromosome segregation, cell cycle, and E2F signaling. Furthermore, depletion of CKAP2L increased the sensitivity of NSCLC cells to alvocidib, a pan-CDK inhibitor, leading to a significant reduction of cell proliferation and an increase in cell death. Altogether, these findings shed light on the molecular mechanisms through which CKAP2L, a protein involved in CIN, promotes cancer progression and suggest that its inhibition represents a novel therapeutic strategy in NSCLC. SIGNIFICANCE: These findings demonstrate the oncogenic function of CKAP2L through regulation of transcription elongation and suggest that targeting CKAP2L could enhance therapeutic response in patients with NSCLC.

Ultrasound-targeted microbubble destruction mediated miR-492 inhibitor suppresses the tumorigenesis in non-small cell lung cancer

Background Ultrasound-targeted microbubble destruction (UTMD) is a novel adjuvant tumor therapeutic method by enhancing exogenous gene transfection to target tissues. This study aims to investigate the role of microRNA-492 (miR-492) in non-small cell lung cancer (NSCLC) and further analyze the effects of UTMD-mediated miR-492 inhibitor on tumorigenesis. Methods The expression of miR-492 was detected by qRT-PCR. Co-transfection of microbubbles and miR-492 inhibitor with Lipofectamine 3000 was performed to achieve UTMD-mediated miR-492 inhibition in NSCLC cells. CCK-8 and Transwell assay were used to determine NSCLC cell proliferation, and the migration and invasion. Result High expression of miR-492 was associated with poor prognosis in NSCLC patients. miR-492 inhibitor suppressed tumor cell proliferation, migration and invasion, and UTMD not only increased the transfection efficiency of miR-492 inhibitor, but also enhance the inhibitory effects on cell biological behaviors. Conclusion The results showed that the expression level of miR-492 was up-regulated in NSCLC tissue samples and cells. Silencing of miR-492 inhibited NSCLC cell proliferation, migration and invasion, and UTMD-mediated miR-492 inhibitor could promote more significant inhibition, which indicated that UTMD-mediated miR-492 inhibitor might provide a novel strategy for the treatment of NSCLC. KEY MESSAGES miR-492 inhibitor inhibited cell proliferation, migration and invasion. UTMD-mediated miR-492 inhibitor can promote more significant inhibition. UTMD-mediated miR-492 inhibitor provide a new strategy for NSCLC.