Treatment Of Non-small Cell Lung Carcinoma Research Articles

Disulfidptosis-related long non-coding RNAs predict prognosis and indicate therapeutic response in non-small cell lung carcinoma

Abstract Objectives Disulfidptosis is a novel form of cell death, whose modulation in tumor cells may present a promising therapeutic strategy for cancer treatment. However, the role of disulfidptosis-related long non-coding RNAs (lncRNAs) in non-small cell lung carcinoma (NSCLC) remains poorly elucidated. This study aims to investigate the prognostic significance of disulfidptosis-related lncRNAs (DRLs) and reveal their relationship to the immune microenvironment of NSCLC. Methods DRLs were identified through co-expression analysis of NSCLC transcriptomic data obtained from the Genomic Data Commons (GDC) data portal. The DRLs prognostic signature (DRLPS) was established using the least absolute shrinkage and selection operator (LASSO) and Cox regression analyses. Samples were separated into high-DS and low-DS groups based on the median disulfidptosis score (DS) of DRLPS. Integrated analyses were then implemented to unveil the association between DRLs and NSCLC microenvironment. These involved the evaluation of functional enrichments, immune cell infiltrations, genetic alterations, and drug sensitivity. Results A prognostic signature was developed based on six prognostic DRLs, which are AL606489.1, LINC00857, AP003555.1, AP000695.1, AC113346.1, and LINC01615. The Kaplan–Meier survival curves demonstrated the significant association between DRLPS and NSCLC prognosis. The functional enrichment assessment revealed the pivotal involvement of DRLs in immune regulation and metabolism in NSCLC. The low-DS and high-DS subgroups of NSCLC patients exhibited distinct differences in terms of immune infiltration and tumor mutation burden. The potential to predict immunotherapy benefit and drug sensitivity in NSCLC treatments was observed in DRLPS. Conclusions In this study, disulfidptosis-related lncRNAs were identified and their roles in NSCLC were revealed. A novel prognostic signature with the potential to predict drug response in NSCLC treatment was developed.

Detection of MiRNA-126-5p in Non-Small Cell Lung Cancer Cells by Nano-Polymerase Chain Reaction and Its Regulatory Mechanism of Radiation Sensitivity to Cancer Cells

Radiotherapy resistance remains a huge hindrance in treating non-small cell lung carcinoma (NSCLC). Hyperthermia, a treatment method that raises the cell temperature to treat tumors, has been putting in clinical application combined with conventional chemotherapy and radiotherapy to enhance their effectiveness in NSCLC treatment. However, the specific mechanism of this combination therapy has not been extensively researched. In this study, we established a radiation-resistant NSCLC cell line by sequential radiation exposure. It was shown that the combination of hyperthermia and radiotherapy suppressed NSCLC xenograft tumor growth and increased radiation-induced apoptosis. Furthermore, downregulation of miR-126-5p was found in radio-resistant NSCLC cells. The results of bioinformatics analysis based on ENCORI showed that RAD50 is a direct target of miR-126-5p. Overexpressed miR-126-5p increased radiation-induced cell death by suppressing RAD50 expression. Hyperthermia treatment increases miR-126-5p and decreases RAD50, leading to more unrepaired DNA damage and greater cellular death. In conclusion, hyperthermia enhances NSCLC cells’ radio-sensitivity via miR-126-5p/RAD50 axis.

Detection of factors related to treatment reduction in docetaxel and ramucirumab for non-small cell lung cancer treatment

Treatment using docetaxel (DOC) and ramucirumab (RAM) is an effective regimen in second or later line advanced non-small cell lung carcinoma (NSCLC) treatment. However, it induces severe adverse effects, resulting in treatment reduction such as dose reduction and/or discontinuation. This study aimed to reveal the factor(s) associated with treatment reduction in DOC + RAM. We retrospectively evaluated patients with advanced NSCLC (n = 155). Treatment reduction of the second course due to severe adverse effects was conducted in 25.8% of the participants, and relative dose intensity at the second course was 95.7 ± 8.4% for DOC and 91.9 ± 24.8% for RAM. Multivariate logistic regression analyses identified that baseline anemia and prophylactic granulocyte colony-stimulating factor (G-CSF) administration are preventive factors for the reduction (adjusted odds ratio, 0.29; 95% confidence interval, 0.12–0.66; P = 0.004 for baseline anemia, 0.18; 0.08–0.42; P < 0.0001 for prophylactic G-CSF administration). The primary cause of the reduction was febrile neutropenia, and the same factors were identified. Our study revealed that patients with baseline anemia and prophylactic G-CSF administration have less risk for treatment reduction in DOC + RAM for NSCLC treatment.

The Role of Hematopoietic Stem Cells in Lung Cancer Response to Radiation Therapy

Non-small cell lung carcinoma (NSCLC) comprises approximately 85% of all lung cancer cases in the United States. We demonstrated that after radiation therapy (RT), bone marrow-derived hematopoietic stem and progenitor cells (HSPCs) are recruited to the NSCLC tumor microenvironment (TME). These HSPCs seemed to positively affect tumor regrowth as their numbers directly correlated with regrowth rates. The TME is comprised of tumor tissue, stromal cells, immune cells, bone marrow-derived cells, and extra cellular matrix (ECM) proteins and has emerged as one of the predominant defensive weapons with which cancer can resist various forms of therapeutic intervention. The ability of tumor-associated HSPCs to maintain hematopoietic potency in tumors suggested a prominent role of these cells in tumor physiology, however; what was missing was a mechanistic understanding of: 1) how HSPCs participate in tumor growth post-RT and 2) how HSPCs are maintained within tumors. To answer these questions, we established NSCLC tumors in mice using Lewis Lung Carcinoma (LLC) cells and assessed tumor-associated HSPCs activity and molecular changes in the TME following RT. We observed that RT induces the TME to produce colony stimulating factor (CSF)-1, a factor that promotes the differentiation of HSPCs into tumor supportive M2-macrophages. Adoptive transplantation of dsRed labeled HSPCs into tumor bearing mice followed by RT directly showed the differentiation of HSPCs into M2-macrophages and a concomitant increase in the regrowth of tumors post-RT. Use of a therapeutic inhibitor of the CSF-1 receptor (GW2580) prevented HSPC differentiation in to M2-macrophages and significantly decreasing regrowth rates. We next assessed how tumor-associated HSPCs maintain their hematopoietic potency within the TME. Analysis of tumors demonstrated high expression levels of the laminin 5-1-1 isoform, which is known to bind CD49f (integrin alpha 6), a marker of functional HSPCs. Tumors exposed to RT demonstrated significantly reduced expression of both laminin 5-1-1 and CD49f. When bound, CD49f inhibits phosphorylation of focal adhesion kinase (FAK) resulting in maintenance of pluripotent stem cells. Analysis of tumor-associated HSPCs demonstrated significantly higher levels of phosphorylated FAK following tumor exposure to RT. Since RT induces HSPC differentiation in to M2-macophages, this observation suggests that tumor-associated HSPC functionality is maintained through the interaction between laminin 5-1-1- and CD49f. The identification of single HSPCs that differentiated in to M2-macrophages and which expressed phosphorylated FAK supports this conclusion. Taken together, this data province's evidence of a mechanism wherein RT disrupts laminin 5-1-1/CD49f interactions releasing tumor-associated HSPCs from maintenance signals. Concomitantly, RT induces the production of CSF-1 within the TME, which induces these “released” HSPCs to differentiate into tumor supportive M2-macrophages and promote tumor regrowth post-RT. Overall, these studies define a new understanding of tumor biology in which HSPCs are significant mediators of tumor response to RT. These findings also identify new cellular and molecular pathways to target in the treatment of NSCLC to achieve more optimal clinical outcomes.

Diagnosis and Treatment of Advanced ALK Rearrangement-Positive Non-Small-Cell Lung Cancer in Portugal: Results of a National Questionnaire.

Rearrangements in the anaplastic lymphoma kinase (ALK) gene define a molecular subgroup of non-small-cell lung carcinoma (NSCLC) that should be treated with ALK-targeting tyrosine kinase inhibitors (TKIs). This study aimed to portray the Portuguese reality about the diagnosis and treatment of stage IV ALK-positive NSCLC. Institutions that treat lung cancer in Portugal were invited to participate in an anonymous electronic questionnaire. A total of 22/35 geographically dispersed institutions responded. A descriptive statistical analysis of the results was performed. Reflex molecular testing was done in 54.6% of the institutions. Next-generation sequencing (NGS) was the preferred diagnostic method (90.9%). Typically, physicians obtained molecular study results within 14-21days. Alectinib was the most commonly used first-line treatment. For patients with brain metastases, 86.4% of the physicians preferred alectinib and 13.6% preferred first-line brigatinib. In the case of asymptomatic oligoprogression in the central nervous system, 85.7% of physicians performed local treatment and kept the patient on a TKI; if symptomatic, 66.7% gave local treatment and stayed with the TKI, while 28.6% gave local treatment and altered the TKI. For patients with symptomatic systemic progression, 47.6% and 38.1% of physicians prescribed lorlatinib after initial treatment with alectinib or brigatinib, respectively. After progression on lorlatinib, 42.9% of respondents chose chemotherapy and 57.1% requested detection of resistance mutations. NGS is widely used for the molecular characterization of ALK-positive NSCLC in Portugal. The country has access to up-to-date therapy. Overall, national clinical practice follows international recommendations for the diagnosis and treatment of ALK-positive NSCLC.

Comparison of Different ROS1 Immunohistochemistry Clones and Consistency with Fluorescence In Situ Hybridization Results in Non-Small Cell Lung Carcinoma

The study of ROS1 rearrangement in non-small cell lung carcinoma (NSCLC) has gained importance as it enables personalized treatment of NSCLC with tyrosine kinase inhibitors. Therefore, it is important that the ROS1 assessment tests become more standardized. In this study, we compared the two immunohistochemistry (IHC) antibodies (D4D6 and SP384 clones) and consistency with the fluorescence in situ hybridization (FISH) results in NSCLC. To investigate the effectiveness of the commonly used two IHC antibodies (SP384 and D4D6 clones) to detect ROS1 rearrangement in NSCLC. A retrospective cohort study. The study included 103 samples diagnosed with NSCLC, confirmed using IHC and FISH ROS1 results (14 positives, four discordant, and 85 consecutive negatives), with sufficient tissue samples (≥ 50 tumor cells). All samples were initially tested with ROS1-IHC antibodies (D4D6 and SP384 clones); their ROS1 status was then analyzed using the FISH method. Finally, samples with discordant IHC and FISH results were confirmed using the reverse transcription polymerase chain reaction method. The sensitivity of SP384 and D4D6 clones of ROS1 antibody was 100% with a ≥ 1 + cut-off. When the ≥ 2 + cut-off was used, the sensitivity rate for the SP384 clone was 100%, whereas the sensitivity for the D4D6 clone was 42.86%. ROS1 FISH rearranged samples were positive for both clones, but SP384 had generally higher intensity than D4D6. The mean IHC score was + 2 for SP384 and + 1.17 for D4D6. SP384 mostly tended to have a higher IHC score intensity, which made the evaluation easier than D4D6. SP384 has a higher sensitivity than D4D6. However, false positives were found in both clones. There was no significant correlation between ROS1 FISH-positivity percentage with SP384 (p = 0.713, p = 0.108) and D4D6 (p = 0.26, p = -0.323) IHC staining intensity. The staining patterns of both clones were similar (homogeneity/heterogeneity). Our findings show that the SP384 clone is more sensitive than D4D6. However, SP384 can also cause false positive results like D4D6. Knowing the variable diagnostic performance of different ROS1 antibodies before using them in clinical applications is necessary. IHC-positive results should be confirmed using FISH.

Emerging trends and focus on immune checkpoint inhibitors for non-small cell lung cancer treatment: visualization and bibliometric analysis.

Introduction: Lung cancer is the leading cause of cancer-related deaths worldwide, and non-small cell lung carcinoma (NSCLC) accounts for approximately 80% of all cases. Immune checkpoint inhibitors (ICIs) are widely used to treat NSCLC owing to their remarkable efficacy. In this study, we analyzed the scientific collaboration network, defined the hotspots of research on the use of ICIs for NSCLC treatment, analyzed its evolution over the past few years, and forecasted the field's future development using bibliometric analysis and a graphical study. Methods: Research articles and reviews regarding ICIs for NSCLC were retrieved and obtained from the Web of Science Core Collection on 26 September 2022. CtieSpace and VOSviewer were thereafter used to conduct the bibliometric and knowledge-map analysis. Results: We included 8,149 articles for this literature analysis. Our analysis showed that the USA had the highest number of publications and citations. We also noted that research trends in this field have changed drastically over the past 20 years, from the early development of ICIs, such as CTLA-4 inhibitors, to the development of recent ones, such as PD-1 and PD-L1 blockers. Further, the focus of research in this field has also gradually shifted from mechanisms to treatment effects and adverse events, suggesting that the field is maturing. Clinical applications are also being explored, including studies on how to enhance efficacy, reduce adverse effects, and expand to other specific cancer types. Conclusion: To the best of our knowledge, this is the first study to construct a comprehensive knowledge map on ICIs for NSCLC. It can help researchers rapidly grasp the status and focus of current research in this area, offer direction, and serve as a reference for conducting similar studies.

Targeted therapy for cisplatin-resistant lung cancer via aptamer-guided nano-zinc carriers containing USP14 siRNA.

Cisplatin (DDP) is a common therapeutic option for non-small cell lung carcinoma (NSCLC). However, some patients fail to respond to the DDP chemotherapy. Therefore, identifying novel biomarkers to improve the diagnosis and treatment of NSCLC is important. Ubiquitin-specific protease (USP14) is involved in various pathological conditions including cancer; however, the role of USP14 in NSCLC remains elusive. The SELEX technology was used to identify aptamers that specifically recognize DDP-resistant lung cancer cells and couple them with nano-zinc (zinc hydroxide, Zn(OH)2) carriers. USP14 levels were higher in DDP-resistant lung cancer compared to DDP-sensitive lung cancer. The survival rate of lung cancer patients with increased USP14 expression was significantly lower than the survival rate of patients with low USP14 expression. Silencing USP14 increased the tumor antagonistic action of DDP in A549 cisplatin-resistant (A549/DDP) cells, while USP14 overexpression decreased the antagonist effects. Aptamer-targeted nano-zinc carriers were loaded with USP14 siRNA to target DDP-resistant lung cancer cells. Aptamer-targeted nano-zinc carriers containing USP14 siRNA increased the antitumor effects of DDP in A549/DDP cells and mice bearing A549/DDP cells. These results indicate that aptamer-guided nano-zinc carriers may be a potent carrier for the precise treatment of drug-resistant tumors.

Upregulation of long intergenic non-coding RNA LINC00326 inhibits non-small cell lung carcinoma progression by blocking Wnt/β-catenin pathway through modulating the miR-657/dickkopf WNT signaling pathway inhibitor 2 axis

BackgroundLong intergenic non-coding RNA 326 (LINC00326) modulates hepatocarcinogenic lipid metabolism. However, the ability of LINC00326 to modulate the highly aggressive non-small cell lung carcinoma (NSCLC) is unknown. Here, LINC00326 in NSCLC was investigated, together with its effects on tumor malignancy and the underlying mechanisms of action.MethodsLINC00326 levels in tumor tissues and cell lines were measured by Real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) and RNA fluorescence in situ hybridization (FISH). Proliferation and apoptosis were assessed in cell lines by Cell Counting Kit-8 (CCK-8), EdU staining assays and flow cytometry, respectively, and tumor growth was measured in mouse models. Possible microRNA targets of LINC00326 were predicted by bioinformatics and verified by RNA pull-down and immunoprecipitation and luciferase reporter assays. Western blotting was used to evaluate the expression of Wnt/β-catenin-associated proteins.Results LINC00326 was downregulated in tumor tissues and cell lines. Knockdown of LINC00326 stimulated NSCLC cell proliferation and suppressed apoptosis in vitro, as well as enhancing xenograft tumor growth. LINC00326 sponged miR-657, and dickkopf WNT signaling pathway inhibitor 2 (DKK2) was found to be directly targeted by miR-657, with LINC00326 positively regulating its expression through sponging miR-657. The actions of LINC00326 knockdown on proliferation and apoptosis were reversed by stimulation of the miR-657/DKK2 axis. Furthermore, overexpression of miR-657 mitigated DKK2 inhibition on Wnt/β-catenin signaling.ConclusionsLINC00326/miR-657/DKK2 axis signaling blocked tumor-associated functions in NSCLC cells through the targeting Wnt/β-catenin pathway. This suggests that this pathway could be a target for NSCLC treatment.

Programmed Death Ligand-1 Testing in Adenocarcinoma Lung: A Comparative Study of Cell Block versus Biopsy.

Immunotherapy currently stands as a novel treatment option, specifically in cases of advanced non-small cell lung carcinoma (NSCLC). Expression of programmed death ligand-1 (PD-L1) in tumor cells forms the mainstay for the use of anti-PD-L1 monoclonal antibodies in the treatment of NSCLC. The objectives of the study were to assess utility of cell blocks for testing of PD-L1 in adenocarcinoma lung and to compare the expression of PD-L1 in cell blocks and the corresponding biopsy specimens. The current study was a prospective case series that included 20 cases of NSCLC-adenocarcinoma lung. Cases included in the study had biopsies performed from lung masses, along with which cell blocks were prepared from fine needle aspiration cytology (FNAC) samples. Testing for PD-L1 was done using the monoclonal PD-L1 antibody, SP-263 clone on the Ventana Benchmark XT system. PD-L1 expression was assessed only in the tumor cells, and cases with >1% expression, cytoplasmic or membranous, in tumor cells were categorized as positive. PD-L1 expression was identified in the biopsy samples of tumor cells of 20% of cases (n = 4/20). In the corresponding cell blocks, PD-L1 expression was identified in the tumor cells of 15% of cases (n = 3/20). Sensitivity and specificity of cell blocks were 75% and 100%, respectively. Positive and negative predictive values were 100% and 94.12%, respectively. PD-L1 testing has both predictive and prognostic implications. PD-L1 testing in cell block samples is a potential alternative, specifically in cases where biopsy tissue is minimal or unavailable.

Durable responders in advanced NSCLC with elevated TMB and treated with 1L immune checkpoint inhibitor: a real-world outcomes analysis

BackgroundFor patients with advanced non-small cell lung carcinoma (NSCLC), immune checkpoint inhibitor (ICPI) and chemotherapy (chemo) ICPI represent two distinct first-line standard-of-care regimens without clear and established biomarkers to inform...

Gene amplification-driven lncRNA SNHG6 promotes tumorigenesis via epigenetically suppressing p27 expression and regulating cell cycle in non-small cell lung cancer.

Long non-coding RNAs (lncRNAs) have been validated to play essential roles in non-small cell lung carcinoma (NSCLC) progression. In this study, through systematically screening GSE33532 and GSE29249 from Gene Expression Omnibus (GEO) database and bioinformatics analysis, we found the significant upregulation of SNHG6 in NSCLC. The activation of SNHG6 was driven by copy number amplification and high expression of SNHG6 indicated a poor prognosis. Functionally, the knockdown of SNHG6 inhibited NSCLC cell proliferation, migration, and suppressed the G1/S transition of the cell cycle. SNHG6 overexpression had the opposite effects. Mechanically, SNHG6 recruited EZH2 to the promoter region of p27 and increased H3K27me3 enrichment, thus epigenetically repressing the expression of p27, regulating the cell cycle, and promoting tumorigenesis of NSCLC. SNHG6 silencing restrained tumor growth in vivo and suppressed the expressions of cell cycle-related proteins in the G1/S transition. In conclusion, our study uncovered a novel mechanism of SNHG6 activation and its function. SNHG6 can be considered a potential target for the diagnosis and treatment of NSCLC in the future.

TM2, a novel semi-synthetic taxoid, exerts anti-MDR activity in NSCLC by inhibiting P-gp function and stabilizing microtubule polymerization

Taxane agents are of particular interest in non-small cell lung carcinomas (NSCLC) treatment, while multidrug resistance (MDR) mediated by P-glycoprotein (P-gp) limits their clinical efficacy. TM2, a chemically semi-synthesized taxane derivative, exerted significant anti-cancer efficacy in vitro and in vivo, especially against vincristine-resistant and adriamycin-resistant cancer cells. In this study, the anti-cancer effect of TM2 on drug-resistant NSCLC was evaluated both in vitro and in vivo, and the mechanism underlying its anti-MDR activity was further clarified. It was found that TM2 was significantly cytotoxic to cisplatin- and paclitaxel-resistant A549 (human non-small cell lung cancer) cells that overexpressing P-gp, resulting in IC50 values of 0.19 µM and 0.12 µM. TM2 micelles (5mg/kg, 10mg/kg, 20mg/kg, i.v., 21 days) inhibited the growth of MDR xenograft with the maximal inhibitory rate up to 80.4%. Moreover, TM2 caused cell cycle arrest in the G2-M phase and apoptosis in drug-resistant cells through promoting tubulin polymerization, which acted in a way similar to taxane agents. Notably, TM2 acted as a P-gp inhibitor with high binding affinity, which resulted in impaired efflux function through forming H-bonds and ATP hydrolysis to induce P-gp conformational alterations. These findings indicated that TM2 displays anti-MDR activity with the potential for the treatment of NSCLC, which can inhibit P-gp function and stabilize microtubule polymerization.

Identification and verification of hub genes associated with the progression of non-small cell lung cancer by integrated analysis.

Objectives: Lung cancer is one of the most common cancers worldwide and it is the leading cause of cancer-related mortality. Despite the treatment of patients with non-small cell lung carcinoma (NSCLC) have improved, the molecular mechanisms of NSCLC are still to be further explored. Materials and Methods: Microarray datasets from the Gene Expression Omnibus (GEO) database were selected to identify the candidate genes associated with tumorigenesis and progression of non-small cell lung carcinoma. The differentially expressed genes (DEGs) were identified by GEO2R. Protein-protein interaction network (PPI) were used to screen out hub genes. The expression levels of hub genes were verified by GEPIA, Oncomine and The Human Protein Atlas (HPA) databases. Survival analysis and receiver operating characteristic (ROC) curve analysis were performed to value the importance of hub genes in NSCLC diagnosis and prognosis. ENCODE and cBioPortal were used to explore the upstream regulatory mechanisms of hub genes. Analysis on CancerSEA Tool, CCK8 assay and colony formation assay revealed the functions of hub genes in NSCLC. Results: A total of 426 DEGs were identified, including 93 up-regulated genes and 333 down-regulated genes. And nine hub genes (CDC6, KIAA0101, CDC20, BUB1B, CCNA2, NCAPG, KIF11, BUB1 and CDK1) were found to increase with the tumorigenesis, progression and cisplatin resistance of NSCLC, especially EGFR- or KRAS-mutation driven NSCLC. Hub genes were valuable biomarkers for NSCLC, and the overexpression of hub genes led to poor survival of NSCLC patients. Function analysis showed that hub genes played roles in cell cycle and proliferation, and knockdown of hub genes significantly inhibited A549 and SPCA1 cell growth. Further exploration demonstrated that copy number alterations (CNAs) and transcription activation may account for the up-regulation of hub genes. Conclusion: Hub genes identified in this study provided better understanding of molecular mechanisms within tumorigenesis and progression of NSCLC, and provided potential targets for NSCLC treatment as well.

Cytokines and Chemokines expression in non-small cell lung carcinoma: diagnosis and therapeutic responses

Non-small cell lung carcinoma (NSCLC) being multifaceted, it acquires genetic and epigenetic variations. These changes tend to control differentiation, proliferation, invasion, and metastasis of tumors. Surgery considered the most effective treatment for NSCLC in the initial stage, about 70 to 80% of patients are not convinced about it essentially because of locoregional tumor extension, extrathoracic spread, or poor physical and functional condition when diagnosed. Cytokines have proved to be successful in cancer treatment, but the impact of certain promising targets on different immune cell populations is still unknown. In the present study, a total of 250 papers including 230 research papers and 20 review papers, extracted from PubMed and Scopus and published from December 31, 1995, to December 31 2021, are reviewed. The most important involved-chemokines in lung cancer including α-chemokine (CC), β-chemokine (CXC), γ-chemokine (C), and δ-chemokine (CX3C). While essential cytokines in lung cancer including TNF-α, IFN- γ, TGF-β and interleukins such as IL-6, IL-1β, IL-8, and IL-18 are introduced. The pathological role of such chemokines and cytokines in cancer signaling pathways are investigated.

Non-Small Cell Lung Cancer; Review of Mutations and Tyrosine Kinase Inhibitors

Lung cancer is the leading cause of cancer-related death in the United States and the incidence of this in never smokers is about 15-20% in males and about 50% in females. Non-small cell lung carcinoma (NSCLC) constitutes about 75% to 80% of these cancers and is more common than small cell lung carcinoma (SCLC) in never smokers. Treatment of NSCLC has been rapidly evolving with the discovery of targetable mutations like EGFR, and ALK. Despite this, prognosis of NSCLC remains guarded given diagnosis at an advanced stage as well as patient factors like age and comorbidities. The standard of care should include therapy customized to suit the patient. In this review article we report the first known case of checkpoint mutation seen in a patient with NSCLC and summarize the common mutations along with targeted therapy with tyrosine kinase inhibitors.

The prognostic role of PD-1, PD-L1, ALK, and ROS1 proteins expression in non-small cell lung carcinoma patients from Egypt

BackgroundProgrammed death ligand-1 (PD-L1), anaplastic lymphoma kinase (ALK), and c-ros oncogene1 (ROS1) expression may influence the prognosis of non-small cell lung carcinoma (NSCLC). We aimed to investigate the prognostic and predictive significance of PD-1/PD-L1 along with c-ros ROS1 and ALK in NSCLC patients.MethodsImmunohistochemistry used to identify ALK, ROS1, PD-1, and PD-L1 proteins expression as well as ROS1 rearrangement via fluorescence in situ hybridization, in 70 NSCLC patients. Results were related to clinicopathological feature, survival, and treatment response.ResultsExpression of ROS1, ALK, PD-1, and PD-L1 and ROS1-rearrangement were detected in 18.57%, 54.29%, 84.29%, 87.14%, and 15.71% of the cases, respectively. No association was found between ROS1, PD-1, and PD-L1 and any clinicopathological features, survival, or treatment outcome. ALK expression significantly associated with stage-IV and left-sided tumors. Epidermal growth factor receptor (EGFR) mutation and ALK-positive patients had significantly reduced progression-free survival than patients with wild type EGFR [HR: 1.99, 95% CI: 1.37–2.93, p < 0.001] and negative-ALK expression [HR: 1.46, 95% CI: 1.03–2.07, p = 0.03]. In multivariate analysis, lymph node metastasis, EGFR-mutations, and ALK were independent predictors of NSCLC. PD-L1 expression was significantly correlated with PD-1 but not with ROS1, ALK, or EGFR-mutation.ConclusionPositive ALK expression and EGFR-mutations are independent adverse predictors of NSCLC. Overexpression of PD-1/PD-L1 is not a significant prognostic marker in NSCLC patients receiving chemotherapy, making them susceptible to immunotherapy. Since PD-1/PD-L1 expression is independent to oncogenic driver mutations, future studies into specific immune checkpoint inhibitors combined with targeted therapies for individualized treatment of NSCLC is warranted.Positive ALK expression and EGFR mutations are independent risk factors for NSCLC. Overexpression of PD-1/PD-L1 is not a significant prognostic factor in patients with NSCLC who are receiving chemotherapy, making them immunotherapy susceptible. Given that PD-1/PD-L1 expression is not dependent on oncogenic driver mutations, additional research into specific immune checkpoint inhibitors in combination with targeted therapies for the treatment of NSCLC on an individual basis is warranted.

BAP18 induces growth of non-small-cell lung carcinoma through upregulating transcriptional level of CCND1/2.

To elucidate the biological function of BAP18 (BPTF-associated protein of 18 kDa) in non-small-cell lung carcinoma (NSCLC) and the molecular mechanism. Relative levels of BAP18 in NSCLC tissues were detected by quantitative real-time polymerase chain reaction (qRT-PCR), and its influence on pathological characteristics of NSCLC patients was analyzed. Correlation between BAP18 and Ki67 levels in NSCLC was assessed by Pearson correlation test. Furthermore, Kaplan-Meier curves were depicted for revealing survival difference in NSCLC patients expressing high or low level of BAP18. Relative levels of BAP18, CCND1, CCND2 and CCND3 in A549 and H1299 cells transfected with siBAP18 were determined, as well as colony number. In addition, after knockdown of protein level of BAP18 in A549 and H1299 cells by lentivirus transfection, cell cycle progression was examined. Co-regulation of BAP18 and CCND1/2 on cell growth of NSCLC was finally detected. BAP18 was upregulated in NSCLC tissues, especially cases with advanced stage (III-IV) or large tumor size (>5 cm). BAP18 was closely linked to tumor size, TNM staging and lymphatic metastasis in NSCLC. Knockdown of BAP18 reduced transcriptional levels of CCND1 and CCND2 in A549 and H1299 cells. Furthermore, knockdown of BAP18 delayed transition from G1 to S phase, and weakened growth of NSCLC cells. BAP18 triggers the progression of NSCLC by regulating transcriptional activities of CCND1/2, which may be a potential target for the treatment and diagnosis of NSCLC.

Integrated Network Pharmacology and Experimental Verification to Explore the Molecular Mechanism of Hedysarum Multijugum Maxim–Curcumae Rhizoma Herb Pair for Treating Non-Small Cell Lung Cancer

BackgroundHedysarum Multijugum Maxim–Curcumae Rhizoma (HMMCR), a well-known herb pair in traditional Chinese medicine (TCM), has been widely used for the treatment of various cancers. However, the active components of HMMCR and the underlying mechanism of HMMCR for non-small-cell lung carcinoma (NSCLC) remain unclear.MethodsActive ingredients of HMMCR were detected by liquid chromatography electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS). On this basis, potential targets of HMMCR were obtained from SwissTargetPrediction database. NSCLC-related targets were collected from four public databases (GeneCards, OMIM, TTD, and PharmGkb). The drug ingredients–disease targets network was visualized. The hub targets between HMMCR and NSCLC were further analyzed by protein–protein interaction (PPI), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Subsequently, the results predicted by network pharmacology were further validated via in vitro experiments.ResultsA total of 181 compounds were identified from the aqueous extract of HMMCR. Through network analysis, a compound–target network including 153 active ingredients of HMMCR and 756 HMMCR-NSCLC co-targets was conducted; 6 crucial compounds and 62 hub targets were further identified. The results of KEGG enrichment analysis showed that PI3K/Akt signaling pathway may be the critical pathway of HMMCR in the treatment of NSCLC. The in vitro experiments indicated that HMMCR inhibits the proliferation and migration of NSCLC cells via inactivation of the PI3K/Akt signaling pathway, consistent with the results predicted by network pharmacology.ConclusionIntegrating LC-ESI-MS/MS, network pharmacology approach, and in vitro experiments, this study shows that HMMCR has vital therapeutic effect on NSCLC through multi-compound, multi-target, and multi-pathway, which provides a rationale for using HMMCR for the treatment of NSCLC.

Bax/Bcl-2 Cascade Is Regulated by the EGFR Pathway: Therapeutic Targeting of Non-Small Cell Lung Cancer.

Non-small cell lung carcinoma (NSCLC) comprises 80%–85% of lung cancer cases. EGFR is involved in several cancer developments, including NSCLC. The EGFR pathway regulates the Bax/Bcl-2 cascade in NSCLC. Increasing understanding of the molecular mechanisms of fundamental tumor progression has guided the development of numerous antitumor drugs. The development and improvement of rationally planned inhibitors and agents targeting particular cellular and biological pathways in cancer have been signified as a most important paradigm shift in the strategy to treat and manage lung cancer. Newer approaches and novel chemotherapeutic agents are required to accompany present cancer therapies for improving efficiency. Using natural products as a drug with an effective delivery system may benefit therapeutics. Naturally originated compounds such as phytochemicals provide crucial sources for novel agents/drugs and resources for tumor therapy. Applying the small-molecule inhibitors (SMIs)/phytochemicals has led to potent preclinical discoveries in various human tumor preclinical models, including lung cancer. In this review, we summarize recent information on the molecular mechanisms of the Bax/Bcl-2 cascade and EGFR pathway in NSCLC and target them for therapeutic implications. We further described the therapeutic potential of Bax/Bcl-2/EGFR SMIs, mainly those with more potent and selectivity, including gefitinib, EGCG, ABT-737, thymoquinone, quercetin, and venetoclax. In addition, we explained the targeting EGFR pathway and ongoing in vitro and in vivo and clinical investigations in NSCLC. Exploration of such inhibitors facilitates the future treatment and management of NSCLC.