Downregulated antisense lncRNA ENTPD3-AS1 contributes to the development of lung adenocarcinoma.

The poor outcome of patients with lung adenocarcinoma (LUAD) highlights the importance to identify novel effective prognostic markers and therapeutic targets. Long noncoding RNAs (lncRNAs) have generally been considered to serve important roles in tumorigenesis and the development of various types of cancer, including LUAD. Here, we aimed to investigate the role of ENTPD3-AS1 (ENTPD3 Antisense RNA 1) in LUAD and to explore its potential mechanisms by performing comprehensive bioinformatic analyses. The regulatory effect of ENTPD3-AS1 on the expression of NR3C1 was validated by siRNA-based silencing. The effect of miR-421 on the modulation of NR3C1 was determined by miRNA mimics and inhibitors transfection. ENTPD3-AS1 was expressed at lower levels in tumor parts and negatively correlated with unfavorable prognosis in LUAD patients. It exerted functions as a tumor suppressor gene by competitively binding to oncomir, miR-421, thereby attenuating NR3C1 expression. Transfection of lung cancer A549 cells with miR-421 mimics decreased the expression of NR3C1. Transfection of lung cancer A549 cells with miR-421 inhibitors increased the expression of NR3C1 with lower cellular functions as proliferation and migration via epithelial-mesenchymal transition. In addition, inhibition of ENTPD3-AS1 by siRNA transfection decreased the levels of NR3C1, supporting the ENTPD3-AS1/miR-421/NR3C1 cascade. Moreover, the bioinformatic analysis also showed that ENTPD3-AS1 could interact with the RNA-binding proteins (RBPs), CELF2 and QKI, consequently regulating RNA expression and processing. Taken together, we identified that ENTPD3-AS1 and its indirect target NR3C1 can act as novel biomarkers for determining the prognosis of patients with LUAD, and further study is required.

Upregulated enhancer of rudimentary homolog promotes epithelial­mesenchymal transition and cancer cell migration in lung adenocarcinoma.

Lung adenocarcinoma (LUAD) is one of the deadliest cancers regarding both mortality rate and number of deaths and warrants greater effort in the development of potential therapeutic targets. The enhancer of rudimentary homolog (ERH) has been implicated in the promotion and progression of certain types of cancer. In the present study, ERH was assessed for its expression pattern and survival association with LUAD in public transcriptomic and proteomic databases. Bioinformatic methods and data from websites, including University of Alabama at Birmingham CANcer data analysis Portal and The Cancer Genome Atlas, were utilized to demonstrate the functional behaviors and corresponding pathways of ERH in LUAD. Human A549 and CL1­0 cell lines were used to validate the findings via functional assays. It was demonstrated that the expression of ERH, at both the transcriptomic and proteomic levels, was higher in LUAD compared with in adjacent non­tumor lung tissue and was associated with worse survival prognosis. Moreover, high ERH expression was correlated with more aggressive functional states, such as cell cycle and invasion in LUAD, and the positive ERH­correlated gene set was associated with worse survival and an immunosuppressive tumor microenvironment. Small nuclear ribonucleoprotein polypeptide G was identified as a molecule that potentially interacted with ERH. Lastly, it was demonstrated that ERH promoted epithelial­mesenchymal transition and cell migration in vitro, but not proliferation. In conclusion, higher expression of ERH in LUAD may facilitate cancer progression and confer worse outcomes. Further deep investigation into the role of ERH in LUAD is needed.

Characterization of the pleural microenvironment niche and cancer transition using single-cell RNA sequencing in EGFR-mutated lung cancer.

Background: Lung cancer is associated with a high mortality rate and often complicated with malignant pleural effusion (MPE), which has a very poor clinical outcome with a short life expectancy. However, our understanding of cell-specific mechanisms underlying the pathobiology of pleural metastasis remains incomplete. Methods: We analyzed single-cell transcriptomes of cells in pleural effusion collected from patients with lung cancer and congestive heart failure (as a control), respectively. Soluble and complement factors were measured using a multiplex cytokine bead assay. The role of ferroptosis was evaluated by GPX4 small interfering RNA (siRNA) transfection and overexpression. Results: We found that the mesothelial-mesenchymal transition (MesoMT) of the pleural mesothelial cells contributed to pleural metastasis, which was validated by lung cancer/mesothelial cell co-culture experiments. The ferroptosis resistance that protected cancer from death which was secondary to extracellular matrix detachment was critical for pleural metastasis. We found a universal presence of immune-suppressive lipid-associated tumor-associated macrophages (LA-TAMs) with complement cascade alteration in the MPE of the lung cancer patients. Specifically, upregulated complement factors were also found in the MPE, and C5 was associated with poor overall survival in the lung cancer patients with epidermal growth factor receptor mutation. Plasmacytoid dendritic cells (pDCs) exhibited a dysfunctional phenotype and pro-tumorigenic feature in the primary cancer. High expression of the gene set extracted from pDCs was associated with a poor prognosis in the lung cancer patients. Receptor-ligand interaction analysis revealed that the pleural metastatic niche was aggravated by cross-talk between mesothelial cells-cancer cells/immune cells via TNC and ICAM1. Conclusions: Taken together, our results highlight cell-specific mechanisms involved in the pathobiological development of pleural metastasis in lung cancer. These results provide a large-scale and high-dimensional characterization of the pleural microenvironment and offer a useful resource for the future development of therapeutic drugs in lung cancer.

Involvement of ACACA (acetyl-CoA carboxylase α) in the lung pre-metastatic niche formation in breast cancer by senescence phenotypic conversion in fibroblasts.

BACKGROUND: Reprogramming of metabolism is strongly associated with the development of cancer. However, the role of metabolic reprogramming in the remodeling of pre-metastatic niche (PMN), a key step in metastasis, is still unknown. We aimed to investigate the metabolic alternation during lung PMN formation in breast cancer. METHODS: We assessed the transcriptomes and lipidomics of lung of MMTV-PyVT mice by microarray and liquid chromatography-tandem mass mass spectrometry before lung metastasis. The validation of gene or protein expressions was performed by quantitative real-time polymerase chain reaction or immunoblot and immunohistochemistry respectively. The lung fibroblasts were isolated from mice and then co-cultured with breast cancer to identify the influence of cancer on the change of lung fibroblasts in PMN. RESULTS: We demonstrated changes in the lipid profile and several lipid metabolism genes in the lungs of breast cancer-bearing MMTV-PyVT mice before cancer spreading. The expression of ACACA (acetyl-CoA carboxylase α) was downregulated in the lung fibroblasts, which contributed to changes in acetylation of protein's lysine residues and the synthesis of fatty acid. The downregulation of ACACA in lung fibroblasts triggered a senescent and inflammatory phenotypic shift of lung fibroblasts in both in vivo and in vitro models. The senescence-associated secretory phenotype of lung fibroblasts enabled the recruitment of immunosuppressive granulocytic myeloid-derived suppressor cells into the lungs through the production of CXCL1 in the lungs. Knock-in of ACACA prevented lung metastasis in the MMTV-PyVT mouse model, further supporting that ACACA was involved in the remodeling of the lung PMN. CONCLUSIONS: Taken together, these data revealed a mechanism by which ACACA downregulation directed the formation of an immunosuppressive lung PMN in breast cancer.

LINC02323 facilitates development of lung squamous cell carcinoma by miRNA sponge and RBP dysregulation and links to poor prognosis.

BACKGROUND: The poor outcome of patients with lung squamous cell carcinoma (LUSC) highlights the importance of the identification of novel effective prognostic markers and therapeutic targets. Long noncoding RNAs (lncRNAs) have generally been considered to serve important roles in tumorigenesis and the development of various types of cancer, including LUSC. METHODS: Here, we aimed to investigate the role of LINC02323 in LUSC and its potential mechanisms by performing comprehensive bioinformatic analyses. RESULTS: LINC02323 was elevated and positively associated with unfavorable prognosis of LUSC patients. LINC02323 exerted oncogenic function by competitively binding to miR-1343-3p and miR-6783-3p, thereby upregulating L1CAM expression. Indeed, we also determined that LINC02323 could interact with the RNA-binding protein DDX3X, which regulates various stages of RNA expression and processing. CONCLUSION: Taken together, we identified that LINC02323 and its indirect target L1CAM can act as novel biomarkers for determining the prognosis of patients with LUSC and thus deserves further study.

Real-world treatment pattern and prognostic factors of stage IV lung squamous cell carcinoma patients.

Lung squamous cell carcinoma (LUSC) represents a minor proportion of nonsmall cell lung cancer (NSCLC) harboring a poor prognosis. Herein, retrospective medical record research was performed to investigate real-world treatment patterns and identify the prognostic factors among LUSC patients. A total of 173 patients with a median age of 68 years were enrolled for analysis. Males were predominant (n = 143, 83%) and current or ex-smokers contributed to 78% of the entire cohort. Pleura and lung were the most common metastatic sites, whereas brain metastasis was only 7%. After diagnosis, however, only 107 patients (62%) had received first-line chemotherapy. In the chemotherapy cohort, median progression-free survival (PFS) and overall survival (OS) were 3.9 and 11.1 months, respectively. After multivariable analysis, bone metastasis and the use of first-line single-agent chemotherapy independently predicted shorter PFS. For baseline characteristics, male sex, metastasis to lung, pleura, liver, and bone independently predicted worse OS. Regarding the treatment pattern, patients who had undergone standard first-line doublet therapy and employed targeted therapies after disease progression linked to longer OS. In the real world, even those who underwent chemotherapy still had poor outcome. The findings may help clinicians to orchestrate the treatment strategies for LUSC patients and provide further direction of large-scale studies.

Characterization of the Oncogenic Potential of Eukaryotic Initiation Factor 4A1 in Lung Adenocarcinoma via Cell Cycle Regulation and Immune Microenvironment Reprogramming.

Lung adenocarcinoma (LUAD) is a common type of lung cancer. Although the diagnosis and treatment of LUAD have significantly improved in recent decades, the survival for advanced LUAD is still poor. It is necessary to identify more targets for developing potential agents against LUAD. This study explored the dysregulation of translation initiation factors, specifically eukaryotic initiation factors 4A1 (EIF4A1) and EIF4A2, in developing LUAD, as well as their underlying mechanisms. We found that the expression of EIF4A1, but not EIF4A2, was higher in tumor tissue and associated with poor clinical outcomes in LUAD patients. Elevated expression of EIF4H with poor prognosis may potentiate the oncogenic role of EIF4A1. Functional enrichment analysis revealed that upregulation of EIF4A1 was related to cell cycle regulation and DNA repair. The oncogenic effect of EIF4A1 was further elucidated by Gene Set Variation Analysis (GSVA). The GSVA score of the gene set positively correlated with EIF4A1 was higher in tumors and significantly associated with worse survival. In the meantime, gene set enrichment analysis (GSEA) also indicated that elevated EIF4A1 expression in LUAD patients was associated with a decreased infiltration score for immune cells by reducing anticancer immune cell types and recruiting immunosuppressive cells. Consistent with the results, the GSVA score of genes whose expression was negatively correlated with EIF4A1 was lower in the tumor tissue of LUAD cases with worse clinical outcomes and was strongly associated with the disequilibrium of anti-cancer immunity by recruiting anticancer immune cells. Based on the results from the present study, we hypothesize that the dysregulation of EIF4A1 might be involved in the pathophysiology of LUAD development by promoting cancer growth and changing the tumor immune microenvironment. This can be used to develop potential diagnostic biomarkers or therapeutic targets for LUAD.

The Therapeutic Potential of ADAMTS8 in Lung Adenocarcinoma without Targetable Therapy.

Lung cancer is well known for its high mortality worldwide. The treatment for advanced lung cancer needs more attention to improve its survival time. A disintegrin and metallopeptidase with thrombospondin motifs 8 (ADAMTS8) has been linked to several cancer types. However, its role in lung cancer is worthy of deep investigation to promote novel drug development. This study took advantage of RNA-seq and bioinformatics to verify the role that ADAMTS8 plays in lung cancer. The functional assays suggested that ADAMTS8 mediates invasion and metastasis when expressed at a low level, contributing to poor overall survival (OS). The expression of ADAMTS8 was under the regulation of GATA Binding Protein 1 (GATA1) and executed its pathologic role through Thrombospondin Type 1 Domain Containing 1 (THSD1) and ADAMTS Like 2 (ADAMTSL2). To define the impact of ADAMTS8 in the lung cancer treatment strategy, this study further grouped lung cancer patients in the TCGA database into mutated epidermal growth factor receptor (EGFR)/wild-type EGFR and programmed death ligand 1 (PD-L1) high/low groups. Importantly, the expression of ADAMTS8 was correlated positively with the recruitment of anticancer NKT cells and negatively with the infiltration of immunosuppressive Treg and exhausted T cells. The results indicated that lung cancer patients with higher ADAMTS8 levels among wild-type EGFR or low PD-L1 groups survive longer than those with lower levels do. This study indicates that ADAMTS8 might be a treatment option for patients with lung adenocarcinoma who lack efficient targeted or immunotherapies.

Downregulated ADAMTS1 Incorporating A2M Contributes to Tumorigenesis and Alters Tumor Immune Microenvironment in Lung Adenocarcinoma.

Lung adenocarcinoma (LUAD) still holds the most dreadful clinical outcomes worldwide. Despite advanced treatment strategies, there are still some unmet needs. Next-generation sequencing of large-scale cancer genomics discovery projects combined with bioinformatics provides the opportunity to take a step forward in meeting clinical conditions. Based on in-house and The Cancer Genome Atlas (TCGA) cohorts, the results showed decreased levels of ADAMTS1 conferred poor survival compared with normal parts. Gene set enrichment analyses (GSEA) indicated the negative correlation between ADAMTS1 and the potential roles of epithelial-mesenchymal transition (EMT), metastasis, and poor prognosis in LUAD patients. With the knockdown of ADAMTS1, A549 lung cancer cells exhibited more aggressive behaviors such as EMT and increased migration, resulting in cancer metastasis in a mouse model. The pathway interaction network disclosed the linkage of downregulated α2-macroglobulin (A2M), which regulates EMT and metastasis. Furthermore, immune components analysis indicated a positive relationship between ADAMTS1 and the infiltrating levels of multiple immune cells, especially anticancer CD4+ T cells in LUAD. Notably, ADAMTS1 expression was also inversely correlated with the accumulation of immunosuppressive myeloid-derived suppressor cells and regulatory T cells, implying the downregulated ADAMTS1 mediated immune adjustment to fit the tumor survival disadvantages in LUAD patients. In conclusion, our study indicates that ADAMTS1 interacts with A2M in regulating EMT and metastasis in LUAD. Additionally, ADAMTS1 contributes to poor prognosis and immune infiltration in LUAD patients.

Single-Cell Transcriptomic Profiles of Lung Pre-Metastatic Niche Reveal Neutrophil and Lymphatic Endothelial Cell Roles in Breast Cancer.

The establishment of a pre-metastatic niche (PMN) is critical for cancer metastasis. However, it remains unclear as to which phenotypes induce changes in the PMN. Single-cell transcriptomic profiling of all cells of the lung in cancer-bearing MMTV-PyVT mice revealed an increased infiltration of N2-type neutrophils and classical monocytes associated with chronic inflammation; notably, lung neutrophils isolated from mice with primary cancer exhibited similar N2-type phenotypes and expressed high levels of inflammatory and angiogenic factors. We also discovered a new cluster of Ki67-upregulated lymphatic endothelial cells (ECs) that activated several cell division-related pathways. Receptor-ligand interactions within the lung potentially mediated PMN formation; these were exemplified by the cross talk of lymphatic EC-N2-type neutrophil via S100A6. In vitro study revealed S100A6 impaired EC tight junction and increased the transendothelial migration of neutrophils. Our results highlight the molecular mechanisms that shape lung PMN and inspire preventive strategies for lung metastasis in breast cancer.

Different Tyrosine Kinase Inhibitors Used in Treating EGFR-Mutant Pulmonary Adenocarcinoma with Brain Metastasis and Intracranial Intervention Have No Impact on Clinical Outcomes.

Brain metastasis in patients with non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations is a factor of poor prognosis. We conducted a retrospective study to determine the optimal treatment strategy for EGFR-mutant NSCLC patients with brain metastasis receiving or not receiving intracranial intervention. A total of 186 patients treated with an EGFR TKI were enrolled in the study, and 79 (42%) received intracranial intervention. Patients who received intracranial intervention and those who did not had a similar treatment response rate (RR), progression-free survival (PFS) (median PFS: 11.0 vs. 10.0 months, p = 0.4842), and overall survival (OS) (median OS: 23.0 vs. 23.2 months, p = 0.2484). Patients treated with gefitinib, erlotinib, afatinib, or osimertinib had a similar RR (63%, 76%, 81%, or 100%, respectively, p = 0.1390), but they had significantly different PFS (median PFS: 7.5, 10.0, 14.8 months, or not reached, respectively, p = 0.0081). In addition, OS tended to be different between different EGFR TKI treatments (median OS of 19.2, 23.7, or 33.0 months for gefitinib, erlotinib, or afatinib treatments, respectively, p = 0.0834). Afatinib and osimertinib both demonstrated significantly longer PFS than gefitinib in a Cox regression model. Graded prognostic assessment (GPA) versions 2017 and 2022 stratified patients with different OS; patients with higher GPA index scores had significantly longer OS (p = 0.0368 and 0.0407 for version 2017 and 2022, respectively).

Ladinin 1 Shortens Survival via Promoting Proliferation and Enhancing Invasiveness in Lung Adenocarcinoma.

Lung cancer is one of the deadliest cancers worldwide, including in Taiwan. The poor prognosis of the advanced lung cancer lies in delayed diagnosis and non-druggable targets. It is worth paying more attention to these ongoing issues. Public databases and an in-house cohort were used for validation. The KM plotter was utilized to discover the clinical significance. GSEA and GSVA were adopted for a functional pathway survey. Molecular biological methods, including proliferation, migration, and the EMT methods, were used for verification. Based on public databases, the increased expression of Ladinin 1 (LAD1) was presented in tumor and metastatic sites. Furthermore, an in-house cohort revealed a higher intensity of LAD1 in tumor rather than in normal parts. The greater the expression of LAD1 was, the shorter the duration of lung adenocarcinoma (LUAD) patient survival. Moreover, the association of B3GNT3 with LAD1 affected the survival of LUAD patients. Functional analyses using GSEA and GSVA revealed the associations with survival, migration, invasion, and EMT. Biologic functions supported the roles of LAD1 in proliferation via the cell cycle and migration in EMT. This study reveals that LAD1 plays a major role in regulating proliferation and migration in lung cancer and impacts survival in LUAD. It is worth investing in further studies and in the development of drugs targeting LAD1.

miR-150-5p-Containing Extracellular Vesicles Are a New Immunoregulator That Favor the Progression of Lung Cancer in Hypoxic Microenvironments by Altering the Phenotype of NK Cells.

Natural killer (NKs) cells are cytotoxic effector cells, which can modulate tumor metastasis according to their function; however, the role of NK cells in lung cancer has not been extensively investigated. In this study, we determined the functional profiles of NK cells in a hypoxic tumor microenvironment (TME) of lung cancer. We revealed CD226 downregulation and functional repression of NK cells after hypoxic lung cancer priming and we then investigated their interaction with extracellular vesicles (EVs) and miR-150-5p. We also found that NK cells from lung cancer patients had lower expression of CD226 on their surface and exhibited a pro-inflammatory, pro-angiogenic and tumorigenesis phenotype by expressing VEGF, CXCL1, CXCL8, S100A8 and MMPs. Moreover, inhibition of miR-150 improved tumor surveillance by reversing CD226 expression and subsequently reinstating cytotoxic NK cell activity in an animal model. Our study introduces a new scenario for the pro-inflammatory and pro-angiogenic activities of NK cells in the hypoxic TME in lung cancer.

First-Line Anaplastic Lymphoma Kinase (ALK) Inhibitors for ALK-Positive Lung Cancer in Asian Populations: Systematic Review and Network Meta-Analysis.

Various anaplastic lymphoma kinase inhibitors (ALKIs) have been approved for first-line use in treating anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). To date, no head-to-head comparison of these newer generation ALKIs has been made, and different efficacies of ALKIs may present across ethnicity. This study aims to compare newer generation ALKIs for treatment efficacy in Asian groups using network meta-analysis. Phase II/III trials that enrolled treatment-naïve Asian ALK-rearranged NSCLC patients treated by ALKIs were included. Progression-free survival (PFS) and overall response rate (ORR) of each trial were extracted as indicators of drug efficacy. Surfaces under cumulative ranking curves (SUCRAs) were calculated as a numeric presentation of the overall ranking associated with each agent. After a systematic literature review, six phase III clinical trials were included. Our results showed that newer generation ALKIs, such as alectinib, brigatinib, ensartinib, and lorlatinib, all demonstrated superior efficacy to crizotinib. Among those, ensartinib exhibited the best overall SUCRA value and ranked first among all agents. According to our network meta-analysis, ensartinib may currently be the most effective first-line treatment for Asian patients with ALK-positive NSCLC. However, this conclusion needs further validation by a larger scale of clinical trials or posthoc analysis of Asian populations. Moreover, in our comparison, low-dose alectinib (300 mg twice daily) exhibited an efficacy profile similar to a higher dose regimen in Asian populations.

Cooperation Between Cancer and Fibroblasts in Vascular Mimicry and N2-Type Neutrophil Recruitment via Notch2-Jagged1 Interaction in Lung Cancer.

BACKGROUND: Angiogenesis is required for tumor development and metastasis, which is a major part in a pro-tumor microenvironment. Vascular mimicry (VM) is a process in which cancer cells, rather than endothelia, create an alternative perfusion system to support the tumor progression. OBJECTIVES: To validate the role of VM and to develop a strategy to inhibit angiogenesis in lung cancer. METHODS: In this study, we utilized lung cancer samples to verify the existence of VM and conducted several experimental methods to elucidate the molecular pathways. RESULTS: H1299 and CL1-0 lung cancer cells were unable to form capillary-like structures. VM formation was induced by cancer-associated fibroblast (CAFs) in both in vitro and in vivo experiments. Notch2-Jagged1 cell-cell contact between cancer cells and CAFs contributes to the formation of VM networks, supported by Notch intracellular domain (NICD) 2 nuclear translocation and N2ICD target gene upregulated in lung cancer cells mixed with CAFs. The polarization of tumor-promoting N2-type neutrophil was increased by VM networks consisting of CAF and cancer cells. The intravasation of cancer cells and N2-type neutrophils were increased because of the loose junctions of VM. Disruption of cancer cell-CAF connections by a γ-secretase inhibitor enforced the anticancer effect of anti-vascular endothelial growth factor antibodies in a mouse model. CONCLUSION: This study provides the first evidence that CAFs induce lung cancer to create vascular-like networks. These findings suggest a therapeutic opportunity for improving antiangiogenesis therapy in lung cancer.

Amine oxidase, copper containing 3 exerts anti­mesenchymal transformation and enhances CD4+ T­cell recruitment to prolong survival in lung cancer.

Lung cancer remains notorious for its poor prognosis. Despite the advent of tyrosine kinase inhibitors and immune checkpoint inhibitors, the probability of curing the disease in lung cancer patients remains low. Novel mechanisms and treatment strategies are needed to provide hope to patients. Advanced strategies of next generation sequencing (NGS) and bioinformatics were used to analyze normal and lung cancer tissues from lung cancer patients. Amine oxidases have been linked to leukocyte migration and tumorigenesis. However, the roles of amine oxidases in lung cancer are not well­understood. Our results indicated that amine oxidase, copper containing 3 (AOC3) was significantly decreased in the tumor tissue compared with the normal tissue, at both the mRNA and protein level, in the included lung cancer patients and public databases. Lower expression of AOC3 conferred a poorer survival probability across the different cohorts. Epigenetic silencing of AOC3 via miR­3691­5p caused tumor promotion and progression by increasing migration and epithelial­mesenchymal transition (EMT). Furthermore, knockdown of AOC3 caused less CD4+ T­cell attachment onto lung cancer cells and reduced transendothelial migration in vitro, as well as reducing CD4+ T­cell trafficking to the lung in vivo. In conclusion, the present study revealed that downregulation of AOC3 mediated lung cancer promotion and progression, as well as decrease of immune cell recruitment. This novel finding could expand our understanding of the dysregulation of the tumor immune microenvironment and could help to develop a novel strategy for the treatment of lung cancer.

The Downregulation of LSAMP Expression Promotes Lung Cancer Progression and Is Associated with Poor Survival Prognosis.

Lung cancer has been a leading cause of cancer-related death for decades and therapeutic strategies for non-driver mutation lung cancer are still lacking. A novel approach for this type of lung cancer is an emergent requirement. Here we find that loss of LSAMP (Limbic System Associated Membrane Protein), compared to other IgLON family of proteins NTM (Neurotrimin) and OPCML (OPioid-binding Cell adhesion MoLecule), exhibits the strongest prognostic and therapeutic significance in predicting lung adenocarcinoma (LUAD) progression. Lower expression of LSAMP and NTM, but not OPCML, were found in tumor parts compared with normal parts in six LUAD patients, and this was validated by public datasets, Oncomine® and TCGA. The lower expression of LSAMP, but not NTM, was correlated to shorter overall survival. Two epigenetic regulations, including hypermethylation and miR-143-3p upregulation but not copy number variation, were associated with downregulation of LSAMP in LUAD patients. Pathway network analysis showed that NEGR1 (Neuronal Growth Regulator 1) was involved in the regulatory loop of LSAMP. The biologic functions by LSMAP knockdown in lung cancer cells revealed LSMAP was linked to cancer cell migration via epithelial-mesenchymal transition (EMT) but not proliferation nor stemness of LUAD. Our result showed for the first time that LSAMP acts as a potential tumor suppressor in regulating lung cancer. A further deep investigation into the role of LSAMP in lung cancer tumorigenesis would provide therapeutic hope for such affected patients.

Lower starting dose of afatinib for the treatment of metastatic lung adenocarcinoma harboring exon 21 and exon 19 mutations.

BACKGROUND: Afatinib has shown favorable response rates (RRs) and longer progression free survival (PFS) in lung cancer patients harboring EGFR mutations compared with standard platinum-based chemotherapy. However, serious adverse drug reactions (ADRs) limit the clinical application of afatinib. METHODS: We designed a retrospective study, enrolling all patients with metastatic lung adenocarcinoma who were diagnosed and treated with 30 or 40 mg daily afatinib as their initial treatment in three Kaohsiung Medical University-affiliated hospitals in Taiwan. RESULTS: A total of 179 patients were enrolled in the study, of which 102 (57%) and 77 (43%) received 30 mg and 40 mg afatinib daily as their initial treatment, respectively. The patients initially using 30 mg afatinib daily had a similar RR (75% vs. 83%, p = 0.1672), median PFS (14.5 vs. 14.8 months, log-rank p = 0.4649), and median OS (34.0 vs. 25.2 months, log-rank p = 0.5982) compared with those initially using 40 mg afatinib daily. Patients initially receiving 30 mg afatinib daily had fewer ADRs compared with those using 40 mg daily. The overall incidence of moderate and severe ADRs was significantly lower in patients receiving 30 mg afatinib daily compared with those using 40 mg daily (49% vs. 77%, p = 0.002); similar findings was observed in terms of severe ADRs (7% vs. 24%, p < 0.0001). CONCLUSION: Patients receiving 30 mg afatinib daily as their initial treatment had similar RR, PFS, OS, but significantly fewer serious ADRs, as compared with those using 40 mg as their starting dose.