Target For Lung Cancer Therapy Research Articles

Vaccine for Targeted Therapy of Lung Cancer: Advances and Developments.

Considering that lung cancer is a leading global perpetrator, novel treatment approaches must be investigated. Due to the broad spectrum of lung cancer, conventional therapies including chemotherapy, radiotherapy, and surgeries, are not always effective and can have adverse consequences. The present study's overarching objective was to enhance the development of a personalized vaccine for targeted lung cancer therapy. Vaccination functions by eliciting a strong and targeted immune response defense by taking advantage of the specific antigens that are expressed by lung cancer cells. Crucial antigens associated with tumor cells have been identified with the recognition of the genetic and immunological circumstances of lung cancer in this review. The vaccine includes these antigens to prime the immune system, directing it toward recognizing and attacking cancerous cells. In this review, we have addressed the possible benefits of a targeted vaccine strategy, which include a reduction in off-target effects and an improvement in health outcomes for patients. These studies highlight the promise of a tailored vaccine in a novel way for the treatment of lung cancer. The integration of molecular profiling and immunological insights offers a rationale for the design and implementation of personalized vaccines. While challenges exist, the promise of improved treatment outcomes and reduced side effects positions targeted vaccine therapy as a compelling avenue for advancing lung cancer treatment.

Genome-Wide Analysis Identifies Nuclear Factor 1C as a Novel Transcription Factor and Potential Therapeutic Target in SCLC

IntroductionRecent insights regarding mechanisms mediating stemness, heterogeneity, and metastatic potential of lung cancers have yet to be fully translated to effective regimens for the treatment of these malignancies. This study sought to identify novel targets for lung cancer therapy. MethodsTranscriptomes and DNA methylomes of 14 SCLC and 10 NSCLC lines were compared with normal human small airway epithelial cells (SAECs) and induced pluripotent stem cell (iPSC) clones derived from SAEC. SCLC lines, lung iPSC (Lu-iPSC), and SAEC were further evaluated by DNase I hypersensitivity (DHS-seq). Changes in chromatin accessibility and depths of transcription factor (TF) footprints were quantified using Bivariate analysis of Genomic Footprint. Standard techniques were used to evaluate growth, tumorigenicity, and changes in transcriptomes and glucose metabolism of SCLC cells after NFIC knockdown and to evaluate NFIC expression in SCLC cells after exposure to BET inhibitors. ResultsSignificant commonality of transcriptomes and DNA methylomes was observed between Lu-iPSC and SCLC; however, this analysis was uninformative regarding pathways unique to lung cancer. Linking results of DNase I hypersensitive site sequencing to RNA sequencing enabled identification of networks not previously associated with SCLC. When combined with footprint depth, NFIC, a transcription factor not previously associated with SCLC, had the highest score of occupancy at open chromatin sites. Knockdown of NFIC impaired glucose metabolism, decreased stemness, and inhibited growth of SCLC cells in vitro and in vivo. ChIP-seq analysis identified numerous sites occupied by BRD4 in the NFIC promoter region. Knockdown of BRD4 or treatment with Bromodomain and extra-terminal domain (BET) inhibitors (BETis) markedly reduced NFIC expression in SCLC cells and SCLC PDX models. Approximately 8% of genes down-regulated by BETi treatment were repressed by NFIC knockdown in SCLC, whereas 34% of genes repressed after NFIC knockdown were also down-regulated in SCLC cells after BETi treatment. ConclusionsNFIC is a key TF and possible mediator of transcriptional regulation by BET family proteins in SCLC. Our findings highlight the potential of genome-wide chromatin accessibility analysis for elucidating mechanisms of pulmonary carcinogenesis and identifying novel targets for lung cancer therapy.

Abstract 988: Genome-wide repeat landscapes in cancer and cell-free DNA

Abstract Introduction: Repeat sequences comprise >50% of the human genome and structural and epigenetic changes in these regions are implicated in cancer. However, no systematic analysis of the compendium of repeat sequences has ever been performed in human cancer or cell-free DNA (cfDNA), largely due to the inability to identify and quantify repeat sequences genome-wide. We describe here the first comprehensive analysis of genome-wide repeat landscapes in cancer and demonstrate their utility in cfDNA liquid biopsies. Methods: We developed ARTEMIS (Analysis of RepeaT EleMents in dISease) an alignment-free, genome-wide approach for analyzing repeat landscapes in short read sequencing. This approach uses a de novo search of short sequences (kmers) in the telomere to telomere (chm13) reference genome to identify 1.2 billion 24-mers uniquely defining 1280 individual repeat types occurring genome-wide across 57 subfamilies and 6 families. We analyzed ARTEMIS kmers in whole genome sequences of 525 matched tumor/normal pairs from breast, colorectal, liver, lung, ovarian, cervical, prostate, thyroid, head and neck, gastric, and bladder cancers in the Pan Cancer Analysis of Whole Genomes (PCAWG), and in low coverage (1-2x) whole genome sequences of 1450 cfDNA samples from individuals with and without 8 types of cancer. Results: Analysis of ARTEMIS kmer repeat landscapes in 525 PCAWG tumors identified changes in all 1280 repeat element types, including 820 novel elements not previously known to be altered in cancer. A median of 807 repeat elements (range 246-1280) were altered in each tumor compared to its matched normal. The majority of changes were in repeat elements not previously described as altered in tumorigenesis and were most frequently found within Satellites, LINEs and SINEs, though changes were also observed in LTRs, Transposable Elements, and RNA Elements. A cross-validated cfDNA model using repeat landscapes (ARTEMIS) and fragmentation features (DELFI) detected individuals in a diagnostic cohort (n=287) across all stages of lung cancer with high performance (AUC 0.91, 95% CI 0.88-0.95) and was externally validated in a separate population (n=513). The locked model generated scores that correlated with circulating tumor mutant allele fractions for patients (n=19) undergoing targeted lung cancer therapy (r=0.80, p<2.2e-16), and stratified progression-free survival (p<0.001). ARTEMIS repeat landscape analyses of cfDNA also detected liver cancer in a high-risk cohort (n=208) of individuals with cirrhosis or viral hepatitis (AUC 0.91, 95% CI 0.87-0.95), and identified tissue of origin among seven tumor types (n=423). Conclusions: ARTEMIS reveals genome-wide repeat landscapes in human cancer, including in 820 novel elements not previously known to be altered in tumorigenesis. These repeat landscapes that can now be described are evaluable in the circulation and provide an avenue for noninvasive detection and characterization of cancer. Citation Format: Akshaya Annapragada, Noushin Niknafs, James R. White, Daniel C. Bruhm, Christopher Cherry, Jamie E. Medina, Vilmos Adleff, Carolyn Hruban, Dimitrios Mathios, Zachariah H. Foda, Jillian Phallen, Robert B. Scharpf, Victor E. Velculescu. Genome-wide repeat landscapes in cancer and cell-free DNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 988.

KIAA0101 promotes cisplatin resistance through regulating cell apoptosis in lung cancer cells.

Lung cancer is one of the most server mortality in the world and remains a huge threat to human health. Recently, cisplatin-based chemotherapy represented a common therapeutic strategy, however, cisplatin resistance greatly limits the therapy efficacy. We investigated whether KIAA0101 plays a role in cisplatin resistance of lung cancer cells and its mechanisms of action. The expression of KIAA0101 was evaluated based on comprehensive bioinformatic analysis. KIAA0101 knockdown and overexpression A549 cells were constructed to investigate its effects on cell proliferation and apoptosis induced by cisplatin treatment. Western blot analysis was performed to measure the levels of p53-related apoptosis proteins. We found that KIAA0101 was greatly increased in lung cancer tissues and cells. Knockdown of KIAA0101 suppressed cell proliferation and increased cisplatin-induced apoptosis. Knockdown of KIAA0101 also augmented the cisplatin-induced cell apoptosis signaling pathway. Then p53 was found to account for the role of KIAA0101 in cisplatin resistance. In conclusion, our findings provide a novel factor of KIAA0101 in lung cancer resistance, which suggests as a novel target for lung cancer therapy.

Deciphering the Role of Fatty Acid-Metabolizing CYP4F11 in Lung Cancer and Its Potential As a Drug Target.

Lung cancer is the leading cause of cancer deaths worldwide. We found that the cytochrome P450 isoform CYP4F11 is significantly overexpressed in patients with lung squamous cell carcinoma. CYP4F11 is a fatty acid ω-hydroxylase and catalyzes the production of the lipid mediator 20-hydroxyeicosatetraenoic acid (20-HETE) from arachidonic acid. 20-HETE promotes cell proliferation and migration in cancer. Inhibition of 20-HETE-generating cytochrome P450 enzymes has been implicated as novel cancer therapy for more than a decade. However, the exact role of CYP4F11 and its potential as drug target for lung cancer therapy has not been established yet. Thus, we performed a transient knockdown of CYP4F11 in the lung cancer cell line NCI-H460. Knockdown of CYP4F11 significantly inhibits lung cancer cell proliferation and migration while the 20-HETE production is significantly reduced. For biochemical characterization of CYP4F11-inhibitor interactions, we generated recombinant human CYP4F11. Spectroscopic ligand binding assays were conducted to evaluate CYP4F11 binding to the unselective CYP4A/F inhibitor HET0016. HET0016 shows high affinity to recombinant CYP4F11 and inhibits CYP4F11-mediated 20-HETE production in vitro with a nanomolar IC 50 Cross evaluation of HET0016 in NCI-H460 cells shows that lung cancer cell proliferation is significantly reduced together with 20-HETE production. However, HET0016 also displays antiproliferative effects that are not 20-HETE mediated. Future studies aim to establish the role of CYP4F11 in lung cancer and the underlying mechanism and investigate the potential of CYP4F11 as a therapeutic target for lung cancer. SIGNIFICANCE STATEMENT: Lung cancer is a deadly cancer with limited treatment options. Cytochrome P450 4F11 (CYP4F11) is significantly upregulated in lung squamous cell carcinoma. Knockdown of CYP4F11 in a lung cancer cell line significantly attenuates cell proliferation and migration with reduced production of the lipid mediator 20-hydroxyeicosatetraenoic acid (20-HETE). Studies with the unselective inhibitor HET0016 show a high inhibitory potency of CYP4F11-mediated 20-HETE production using recombinant enzyme. Overall, our studies demonstrate the potential of targeting CYP4F11 for new transformative lung cancer treatment.

The Role of Exosome-Derived microRNA on Lung Cancer Metastasis Progression.

The high mortality from lung cancer is mainly attributed to the presence of metastases at the time of diagnosis. Despite being the leading cause of lung cancer death, the underlying molecular mechanisms driving metastasis progression are still not fully understood. Recent studies suggest that tumor cell exosomes play a significant role in tumor progression through intercellular communication between tumor cells, the microenvironment, and distant organs. Furthermore, evidence shows that exosomes release biologically active components to distant sites and organs, which direct metastasis by preparing metastatic pre-niche and stimulating tumorigenesis. As a result, identifying the active components of exosome cargo has become a critical area of research in recent years. Among these components are microRNAs, which are associated with tumor progression and metastasis in lung cancer. Although research into exosome-derived microRNA (exosomal miRNAs) is still in its early stages, it holds promise as a potential target for lung cancer therapy. Understanding how exosomal microRNAs promote metastasis will provide evidence for developing new targeted treatments. This review summarizes current research on exosomal miRNAs' role in metastasis progression mechanisms, focusing on lung cancer.

Core-triple shells pH-responsive zinc-ferrite nanocomposite: Efficient dual remedy for targeted lung cancer therapy

Core-triple shells pH-responsive zinc-ferrite nanocomposite: Efficient dual remedy for targeted lung cancer therapy

EGFR targeted albumin nanoparticles of oleanolic acid: In silico screening of nanocarrier, cytotoxicity and pharmacokinetics for lung cancer therapy

This study aimed to develop cetuximab (CTX) functionalized albumin nanoparticles (ALB-NPs) of oleanolic acid for EGFR targeted lung cancer therapy. The molecular docking methodology has been applied for a selection of suitable nanocarrier. Various physicochemical parameters like particle size, polydispersity, zeta potential, morphology, entrapment efficiency, and in-vitro drug release of all the ALB-NPs were analyzed. Furthermore, the in-vitro qualitative and quantitative cellular uptake study revealed that higher uptake of CTX conjugated ALB-NPs than nontargeted ALB-NPs in A549 cells. The in-vitro MTT assay revealed that the IC50 value of CTX-OLA-ALB-NPs (4.34 ± 1.90 μg/mL) was significantly reduced (p < 0.001) than OLA-ALB-NPs (13.87 ± 1.28 μg/mL) in A-549 cells. CTX-OLA-ALB-NPs caused apoptosis in A-549 cells at concentrations equivalent to its IC50 value and blocked the cell cycle in the G0/G1 phases. The hemocompatibility, histopathology and lung safety study confirmed the biocompatibility of the developed NPs. In vivo ultrasound and photoacoustic imaging confirmed the targeted delivery of the NPs to lung cancer. The findings demonstrated that CTX-OLA-ALB-NPs have potential for site-specific delivery of OLA for effective and targeted therapy of lung carcinoma.

Pyroptosis: A promising target for lung cancer therapy

Pyroptosis: A promising target for lung cancer therapy

Sulfonylated Indeno[1,2-c]quinoline Derivatives as Potent EGFR Tyrosine Kinase Inhibitors.

The epidermal growth factor receptor (EGFR) has been considered a potential target for lung cancer therapy due to its essential role in regulating the survival and proliferation of cancer cells. Although erlotinib, a potent EGFR tyrosine kinase (EGFR-TK) inhibitor, has been used as the first-line drug for lung cancer treatment, acquired drug resistance caused by the T790M secondary mutation of EGFR-TK inevitably develops after a median response duration of 9-13 months. Thus, the search for promising compounds to effectively target EGFR-TK has become an imperative necessity. In this study, the kinase inhibitory activities of a series of sulfonylated indeno[1,2-c]quinolines (SIQs) against EGFR-TK were experimentally and theoretically investigated. Among the 23 SIQ derivatives studied, eight compounds showed enhanced EGFR-TK inhibitory activity (IC50 values of ca. 0.6-10.2 nM) compared to the known drug erlotinib (IC50 of ∼20 nM). In a cell-based assay in human cancer cell lines with EGFR overexpression (A549 and A431 cells), the eight selected SIQs all showed more significant cytotoxicity against A431 than A549 cells, consistent with the higher EGFR expression in A431 cells. Molecular docking and FMO-RIMP2/PCM calculations revealed that SIQ17 occupies the ATP-binding site of EGFR-TK, where its sulfonyl group is mainly stabilized by C797, L718, and E762 residues. Triplicate 500 ns molecular dynamics (MD) simulations also confirmed the binding strength of SIQ17 in complex with EGFR. Overall, the potent SIQ compounds obtained in this work could be further optimized for developing novel anticancer drug candidates targeting EGFR-TK.

N6-Methyladenosine Promotes Translation of VEGFA to Accelerate Angiogenesis in Lung Cancer.

Methylation of the 5'UTR IRES of VEGFA mRNA increases cap-independent translation via recruitment of the YTHDC2/eIF4GI complex, which stimulates angiogenesis to promote lung tumor growth.

[Progress in the Study of Spindle Assembly Checkpoint in Lung Cancer].

Spindle assembly checkpoint (SAC) is a protective mechanism for cells to undergo accurate mitosis. SAC prevented chromosome segregation when kinetochores were not, or incorrectly attached to microtubules in the anaphase of mitosis, thus avoiding aneuploid chromosomes in daughter cells. Aneuploidy and altered expression of SAC component proteins are common in different cancers, including lung cancer. Therefore, SAC is a potential new target for lung cancer therapy. Five small molecule inhibitors of monopolar spindle 1 (MPS1), an upstream component protein of SAC, have entered clinical trials. This article introduces the biological functions of SAC, summarizes the abnormal expression of SAC component proteins in various cancers and the research progress of MPS1 inhibitors, and expects to provide a reference for the future development of lung cancer therapeutic strategies targeting SAC components.
.

Challenges of EGFR-TKIs in NSCLC and the potential role of herbs and active compounds: From mechanism to clinical practice.

Epidermal growth factor receptor (EGFR) mutations are the most common oncogenic driver in non-small cell lung cancer (NSCLC). Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are widely used in the treatment of lung cancer, especially in the first-line treatment of advanced NSCLC, and EGFR-TKIs monotherapy has achieved better efficacy and tolerability compared with standard chemotherapy. However, acquired resistance to EGFR-TKIs and associated adverse events pose a significant obstacle to targeted lung cancer therapy. Therefore, there is an urgent need to seek effective interventions to overcome these limitations. Natural medicines have shown potential therapeutic advantages in reversing acquired resistance to EGFR-TKIs and reducing adverse events, bringing new options and directions for EGFR-TKIs combination therapy. In this paper, we systematically demonstrated the resistance mechanism of EGFR-TKIs, the clinical strategy of each generation of EGFR-TKIs in the synergistic treatment of NSCLC, the treatment-related adverse events of EGFR-TKIs, and the potential role of traditional Chinese medicine in overcoming the resistance and adverse reactions of EGFR-TKIs. Herbs and active compounds have the potential to act synergistically through multiple pathways and multiple mechanisms of overall regulation, combined with targeted therapy, and are expected to be an innovative model for NSCLC treatment.

Abstract 6556: A gene signature of DNA damage response pathway is predictive of patient clinical outcomes and is associated with tumor immune microenvironment of lung adenocarcinoma

Abstract DNA damage response (DDR) is crucial to prevent the accumulation of DNA lesions that can lead to genomic instability and promote tumorigenesis. Dysregulation of DDR pathways also provides therapeutic opportunities for new cancer therapy. Given that lung cancer displays a high level of genetic mutation and genomic instability, a comprehensive understanding of the dysregulation of DDR genes in lung cancer, especially non-small cell lung cancer (NSCLC) which accounts for 85% of all lung cancer cases, will be critical for identifying new genes contributing to tumorigenesis and novel targets for lung cancer therapy. The goal of this study is to identify novel targets for lung cancer treatment through a comprehensive analysis of DDR genes and its association with patient survival, genomic mutation/instability, tumor immune microenvironment (TIME), and tumor proliferation ability. To this end, we have comprehensively characterized the expression of 276 DDR genes using the Cancer Genome Atlas (TCGA) and other publicly available data of lung adenocarcinoma (LUAD), the most common NSCLC. We found that 36 out of 276 DDR genes are dysregulated with majority being upregulated in tumors and are associated with patient overall survival (OS) and progression free survival (PFS) based on the TCGA LUAD cohort. A gene expression signature, i.e., DDR gene expression dysregulation score (DDRDS), was constructed based on the geometric mean of the differentially expressed genes that were also associated with patient OS. Patients with a higher DDRDS showed significantly worse OS and PFS, more advanced tumor stage, a higher tumor mutational burden (TMB), neoantigen load, and homologous recombination deficiency (HRD) score. In addition, tumors with higher DDRDS displayed an increase in CD4+ activated memory T-cells, CD8+ T- cells, M0 and M1 macrophage, and NK cells, but a decrease in B cells, CD4+ resting memory T-cells, monocytes, and dendritic cells in TIME. Further, these tumors also showed a higher expression of immune check point molecules PD1 and PD-L1. Lastly, gene set enrichment analysis demonstrated that these tumors had significantly increased nuclear division, DNA replication, chromosome segregation, and cell cycles, reflecting the aggressiveness of the disease. Hence, despite the previous studies demonstrating that mutation and deletion defects in DDR genes are frequent in tumors, we found that the dysregulated DDR genes are mainly upregulated, and DDRDS based on the dysregulated expression of DDR genes is associated with the alteration in TMB/HRD/TIME, tumor aggressiveness, and ultimately patient outcomes. These results suggested that patients with a higher tumor DDRDS are associated with poor prognosis but might benefit from immune checkpoint blockade-associated immunotherapy. Citation Format: Xiaoli Zhang, Junran Zhang. A gene signature of DNA damage response pathway is predictive of patient clinical outcomes and is associated with tumor immune microenvironment of lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6556.

Cinobufotalin Induces Ferroptosis to Suppress Lung Cancer Cell Growth by lncRNA LINC00597/hsa-miR-367-3p/TFRC Pathway via Resibufogenin.

Lung cancer is the leading cause of cancer-associated death and the first most diagnosed cancer in the world. More than 2 million new cases are diagnosed and 1.6 million people die due to lung cancer every year. It is urgent to explore novel drugs and approaches for lung cancer treatment. Cinobufotalin is a TCM isolated from dried toad venom, which has been used to treat lung cancer. However, the precise mechanism remains unclear. This study was to investigate the mechanism of cinobufotalin treated in lung cancer. Cell growth was identified by Cell Counting Kit-8 (CCK-8) assay. Besides, ferroptosis of lung cancer cells was determined by intracellular iron content, lactate dehydrogenase (LDH) release and mitochondrial membrane potential. Moreover, RNA levels and proteins were detected by quantitative reverse transcription-PCR (qRT-PCR) and Western blot (WB), respectively. In addition, the regulatory effect of hsa-miR-367-3p on TFRC was confirmed by luciferase reporter assay. This study indicated that cinobufotalin suppressed lung cancer cell growth through resibufogenin. Besides, cinobufotalin induced ferroptosis in lung cancer cells through resibufogenin. Moreover, cinobufotalin increased lncRNA LINC00597 level, whereas it downregulated hsa-miR-367-3p expression in lung cancer cells via resibufogenin. In addition, ferroptosis inducer transferrin receptor (TFRC) was the target of hsa-miR-367-3p, and lncRNA LINC00597 upregulates TFRC expression through sponging hsa-miR-367-3p in lung cancer cells. In summary, this study indicated that cinobufotalin induced ferroptosis to suppress lung cancer cell growth by lncRNA LINC00597/hsa-miR-367-3p/TFRC pathway via resibufogenin might provide novel therapeutic targets for lung cancer therapy.

P21 Genetic Modification as a Tumor-Suppressor Gene: A Future Target in Lung Cancer Therapy?

Lung cancer is one of the most common cancers and the leading cause of cancer death worldwide. Although early diagnosis/screening methods and treatment strategies have developed, lung cancer patient survival rates remain low. However, resistance to chemotherapy and radiotherapy causes tumor recurrence and worsening of the disease, thus being the lead cause of treatment failure. In the growth cycle of lung cancer cells, the highest p21WAF1/CIP1 gene expression was found in early-stage lung cancer and decreased in advanced lung cancer. In addition, the association between CDK inhibitors and patient survival showed that inactivation of the p21WAF1/CIP1 and p16INK4a genes was associated with lower overall survival and poor prognosis. In this review, we will focus on the role of genetic modification in lincRNA-p21 in lung cancer therapy and the importance of a combination therapeutic approach.

Cancer Exosome Loaded with Paclitaxel for Targeted Lung Cancer Therapy

Lung cancer is a serious issue to threat the health of human and the treatment using currently available chemotherapy drug, such as paclitaxel (PTX) is significantly impaired by the poor solubility and targetability. In this study, we used the cancer exosome (CE) derived from lung cancer cell line A549 to load PTX (CE/PTX) and construct a drug delivery system (DDS) for the treatment of A549 tumor in a mice mode. The DDS realized better inhibition on both A549 cells and tumors as compared to commercial PTX formulation (Taxol). Therefore, we believe this strategy can be applied to clinical trials for better cancer treatment.

Cell Therapy with Human Reprogrammed CD8+ T-Cells Has Antimetastatic Effects on Lewis Lung Carcinoma in C57BL/6 Mice.

Using a model of Lewis lung carcinoma (LLC) in vitro and in vivo, we previously demonstrated increased antitumor activity in CD8+ T-cells reprogrammed with an MEK inhibitor and PD-1 blocker. In this follow-up study, we carried out the reprogramming of human CD8+ T-cells (hrT-cell) using the MEK inhibitor and PD-1 blocker and targeted LLC cells. The effects of hrT-cell therapy were studied in a mouse model of spontaneous metastasis of a solid LLC tumor. We found antimetastatic activity of hrT-cells, a decrease in the number of cancer cells and cancer stem cells in the lungs, and an increase in the number of T-cells in the blood (including effector T-cells). Thus, reprogramming of human CD8+ T-cells with an MEK inhibitor and PD-1 blocker with targeted training by tumor target cells is a potential platform for developing a new approach to targeted lung cancer therapy.

Screening of potential microbial markers for lung cancer using metagenomic sequencing.

Lung cancer is the most prevalent cancer with high mortality in China, and it is associated with the dysbiosis of the lung microbiome. This study attempted to screen for specific microorganisms as potential biomarkers for distinguishing benign lung disease from lung cancer. Bronchoalveolar lavage fluid (BALF) sample was selected in the study instead of saliva to avoid contamination with oral microorganisms, and microbial taxonomic and functional differences in BALF samples from patients with lung cancer and those with those from patients with benign lung diseases were performed based on metagenomic next-generation sequencing, for the first time, so that microorganisms other than bacteria could be included. The results showed that the intrasample diversity of malignant samples was different from benign samples, and the microbial differences among malignant samples were smaller, with lower microbial diversity, significantly changed microbial abundance and metabolic functions. Metabolic function analysis revealed amino acid-related metabolism was more prevalent in benign samples, whereas carbohydrate-related metabolism was more prevalent in malignant samples. By LEfSe, Metastat and Random Forest analysis, we identified a series of important differential microorganisms. Importantly, the model combining five key genera plus one tumor marker (neuron-specific enolase) as indicators presented the optimal disease typing performance. Thus results suggest the value of these differential microorganisms enriched in tumors in mechanism research and may be potential new targets for lung cancer therapy. More importantly, the biomarkers identified in this study can be conducive to improve the clinical diagnosis of lung cancer and have good application prospects.

The Role of MRE11 in the IL-6/STAT3 Pathway of Lung Cancer Cells.

MRE11 is a pivotal protein for ATM activation during double-strand DNA break. ATM kinase activations may act as lung cancer biomarkers. The IL-6/STAT3 pathway plays an important role in tumor metastasis, including lung cancer. However, the mechanism between MRE11 and the IL-6/STAT3 pathway is still unclear. In this study, we discovered that MRE11 can interact with STAT3 under IL-6 treatment and regulate STAT3 Tyr705 phosphorylation. After the knockdown of MRE11 in lung cancer cells, we discovered that IL-6 or the conditional medium of THP-1 cells can induce the mRNA expression of STAT3 downstream genes, including CCL2, in the control cells, but not in MRE11-knockdown lung cancer cells. Moreover, CCL2 secretion was lower in MRE11-knockdown lung cancer cells than in control cells after treatment with the conditional medium of RAW264.7 cells. In addition, MRE11 deficiency in lung cancer cells decreases their ability to recruit RAW 264.7 cells. Furthermore, MRE11 is a potential target for lung cancer therapy.