PD-L1 expression testing in non-small cell lung cancer DOI Creative Commons
Cristina Teixidó, Noelia Vilariño, Roxana Reyes

et al.

Therapeutic Advances in Medical Oncology, Journal Year: 2018, Volume and Issue: 10

Published: Jan. 1, 2018

In recent years, immunotherapy has revolutionized and changed the standard of care in patients with advanced non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors, fundamentally those that act by blocking programmed death receptor-1 (PD-1) its ligand ligand-1 (PD-L1) have emerged as novel treatment strategies NSCLC, demonstrating undoubted superiority over chemotherapy terms efficacy. Several these immune modulators recently gained regulatory approval for such nivolumab, atezolizumab pembrolizumab first-line (only latter) second-line settings, more recently, durvalumab maintenance after chemoradiotherapy locally disease. There is consensus PD-L1 expression on tumor cells predicts responsiveness to PD-1 inhibitors several types. Hence evaluated immunohistochemistry (IHC) currently used a clinical decision-making tool support use NSCLC patients. However, value ‘definitive’ biomarker controversial testing puzzled multiple unsolved issues different staining platforms antibodies, type which assessed (tumor versus cells), thresholds PD-L1-positivity, or source timing sample collection. Therefore, newer biomarkers mutation burden neoantigens well reflecting host environment (microbiome) inflamed microenvironment (gene signatures) are being explored reliable accurate alternatives IHC guiding selection NSCLC.

Language: Английский

Molecular basis and rationale for combining immune checkpoint inhibitors with chemotherapy in non-small cell lung cancer DOI
Alessandro Leonetti, Birgit M. M. Wever, Giulia Mazzaschi

et al.

Drug Resistance Updates, Journal Year: 2019, Volume and Issue: 46, P. 100644 - 100644

Published: Sept. 1, 2019

Language: Английский

Citations

174
EMT-Mediated Acquired EGFR-TKI Resistance in NSCLC: Mechanisms and Strategies DOI Creative Commons
Xuan Zhu, Lijie Chen,

Ling Liu

et al.

Frontiers in Oncology, Journal Year: 2019, Volume and Issue: 9

Published: Oct. 11, 2019

Acquired resistance inevitably limits the curative effects of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), which represent classical paradigm molecular-targeted therapies in non-small-cell lung cancer (NSCLC). How to break such a bottleneck becomes pressing problem treatment. The epithelial-mesenchymal transition (EMT) is dynamic process that governs biological changes various aspects malignancies, notably drug resistance. Progress delineating nature this offers an opportunity develop clinical therapeutics tackle towards anticancer agents. Herein, we seek provide framework for mechanistic underpinnings on EMT-mediated acquisition EGFR-TKI resistance, with focus NSCLC, and raise question what therapeutic strategies along line should be pursued optimize efficacy practice.

Language: Английский

Citations

173
Autophagy inhibition potentiates the anti-angiogenic property of multikinase inhibitor anlotinib through JAK2/STAT3/VEGFA signaling in non-small cell lung cancer cells DOI Creative Commons
Lijun Liang,

Kaiyuan Hui,

Chenxi Hu

et al.

Journal of Experimental & Clinical Cancer Research, Journal Year: 2019, Volume and Issue: 38(1)

Published: Feb. 12, 2019

The efficacy and safety of multikinase inhibitor anlotinib have been confirmed in the treatment advanced non-small cell lung cancer (NSCLC). However, direct functional mechanisms tumor lethality mediated by were not fully elucidated, underlying related to resistance remain largely elusive.Cell viability, colony formation, apoptosis growth assays performed examine effect on cells vitro vivo. punctate patterns LC3-I/II detected confocal microscopy. HUVECs motility was using Transwell scratch wound-healing assay. To visualize microvessels, tubular formation assay performed. expression beclin-1 changes JAK2/STAT3/VEGFA pathway western blotting. VEGFA levels supernatant measured ELISA.Anlotinib decreased viability induced Calu-1 A549 cells. Moreover, human autophagy a dose- time-dependent manner. Blocking enhanced cytotoxicity anti-angiogenic ability as evidenced migration, invasion, Co-administration chloroquine (CQ) further reduced level supernatant, compared with that or CQ alone. When rapamycin, JAK2/STAT3 activated elevated, which attenuated after deactivating STAT3 S3I-201. Further vivo studies showed inhibited growth, suppressed pathway, this effect.Anlotinib protective lines. Autophagy inhibition cytotoxic effects anlotinib, potentiated property through signaling.

Language: Английский

Citations

153
Inferring gene expression from cell-free DNA fragmentation profiles DOI
Mohammad Shahrokh Esfahani, Emily G. Hamilton, Mahya Mehrmohamadi

et al.

Nature Biotechnology, Journal Year: 2022, Volume and Issue: 40(4), P. 585 - 597

Published: March 31, 2022

Language: Английский

Citations

137
Lung cancer scRNA-seq and lipidomics reveal aberrant lipid metabolism for early-stage diagnosis DOI Open Access
Guangxi Wang, Mantang Qiu, Xudong Xing

et al.

Science Translational Medicine, Journal Year: 2022, Volume and Issue: 14(630)

Published: Feb. 2, 2022

Lung cancer is the leading cause of mortality, and early detection key to improving survival. However, there are no reliable blood-based tests currently available for early-stage lung diagnosis. Here, we performed single-cell RNA sequencing different cancers found that lipid metabolism was broadly dysregulated in cell types, with glycerophospholipid as most altered metabolism–related pathway. Untargeted lipidomics carried out an exploratory cohort 311 participants. Through support vector machine algorithm-based mass spectrum–based feature selection, identified nine lipids (lysophosphatidylcholines 16:0, 18:0, 20:4; phosphatidylcholines 16:0–18:1, 16:0–18:2, 18:0–18:1, 18:0–18:2, 16:0–22:6; triglycerides 16:0–18:1–18:1) features important detection. Using these features, developed a liquid chromatography–mass spectrometry (MS)–based targeted assay using multiple reaction monitoring. This target achieved 100.00% specificity on independent validation cohort. In hospital-based screening 1036 participants examined by low-dose computed tomography prospective clinical containing 109 participants, reached more than 90.00% sensitivity 92.00% specificity. Accordingly, matrix-assisted laser desorption/ionization MS imaging confirmed selected were differentially expressed tissues situ. method, designated Cancer Artificial Intelligence Detector, may be useful or large-scale high-risk populations prevention.

Language: Английский

Citations

127
Transbronchial mediastinal cryobiopsy in the diagnosis of mediastinal lesions: a randomised trial DOI Open Access
Jing Zhang, Jieru Guo,

Zan‐Sheng Huang

et al.

European Respiratory Journal, Journal Year: 2021, Volume and Issue: 58(6), P. 2100055 - 2100055

Published: May 6, 2021

Background Guidelines recommend endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) as an initial investigatory technique for mediastinal nodal staging in lung cancer. However, EBUS-TBNA can be limited by the inadequacy of intact tissues, which might restrict its diagnostic yield lesions certain aetiologies. We have previously shown that EBUS-guided cryobiopsy provide samples with greater volume. Methods This randomised study determined and safety monitored endosonography diagnosis lesions. Patients a lesion ≥1 cm short axis were recruited. Following identification linear EBUS, fine-needle sequentially performed order. Primary end-points yield, defined percentage patients whom biopsy provided definite diagnosis, procedure-related adverse events. Results In total, 197 enrolled randomly allocated. The overall was 79.9% 91.8% TBNA cryobiopsy, respectively (p=0.001). Diagnostic yields similar metastatic lymphadenopathy (94.1% versus 95.6%, p=0.58), while more sensitive than uncommon tumours (91.7% 25.0%, p=0.001) benign disorders (80.9% 53.2%, p=0.004). No significant differences detected between “TBNA first” “Cryobiopsy groups. observed two cases pneumothorax one case pneumomediastinum. Conclusions Transbronchial under EBUS guidance is safe useful approach offers histological

Language: Английский

Citations

123
KRAS‐G12D mutation drives immune suppression and the primary resistance of anti‐PD‐1/PD‐L1 immunotherapy in non‐small cell lung cancer DOI
Chengming Liu,

Sufei Zheng,

Zhanyu Wang

et al.

Cancer Communications, Journal Year: 2022, Volume and Issue: 42(9), P. 828 - 847

Published: July 11, 2022

Abstract Background Although immune checkpoint inhibitors (ICIs) against programmed cell death protein 1 (PD‐1) and its ligand PD‐L1 have demonstrated potency towards treating patients with non‐small lung carcinoma (NSCLC), the potential association between Kirsten rat sarcoma viral oncogene homolog ( KRAS ) substitutions efficacy of ICIs remains unclear. In this study, we aimed to find point mutations in gene resistant elucidate resistance mechanism. Methods The variant status was explored a clinical cohort n = 74), confirmed mouse model. addition, tumor microenvironment (TIME) ‐mutant NSCLC, such as CD8 + tumor‐infiltrating lymphocytes (TILs) level, investigated. Cell lines expressing classic were used explore signaling pathway activation involved formation TIME. Furthermore, interventions that improved TIME developed increase responsiveness ICIs. Results We observed inferior ‐G12D‐mutant NSCLC. Based upon transcriptome data immunostaining results from ‐G12D mutation negatively correlated level secretion chemokines CXCL10/CXCL11 led decrease TILs, which turn yielded an immunosuppressive analysis overexpressing further revealed suppressed via P70S6K/PI3K/AKT axis reduced levels by down‐regulating high mobility group A2 (HMGA2) level. Notably, paclitaxel, chemotherapeutic agent, upregulated HMGA2 turn, stimulated CXCL10/CXCL11. Moreover, blockade combined paclitaxel significantly growth compared inhibitor monotherapy model adenocarcinoma. Further analyses treatment enhanced recruitment TILs up‐regulation levels. study also superior chemo‐immunotherapy NSCLC ICI monotherapy. Conclusions Our elucidated molecular mechanism drives immunosuppression enhances Importantly, our findings demonstrate combination chemotherapy may be more effective

Language: Английский

Citations

83
Long non-coding RNAs and exosomal lncRNAs: Potential functions in lung cancer progression, drug resistance and tumor microenvironment remodeling DOI Creative Commons
Maliheh Entezari,

Maryam Ghanbarirad,

Afshin Taheriazam

et al.

Biomedicine & Pharmacotherapy, Journal Year: 2022, Volume and Issue: 150, P. 112963 - 112963

Published: April 22, 2022

Among the different kinds of tumors threatening human life, lung cancer is one that commonly observed in both males and females. The aggressive behavior interactions occurring tumor microenvironment enhances malignancy this tumor. cells have demonstrated capacity developing chemo- radio-resistance. LncRNAs are a category non-coding RNAs do not encode proteins, but their aberrant expression responsible for development, especially cancer. In present review, we focus on lncRNAs exosomal cancer, ability regulating proliferation metastasis. Cell cycle progression molecular mechanisms related to metastasis such as EMT MMPs regulated by lncRNAs. interact with miRNAs, STAT, Wnt, EZH2, PTEN PI3K/Akt signaling pathways affect cells. demonstrate tumor-suppressor tumor-promoting functions They can be considered biomarkers body fluids potential tools minimally invasive diagnosis. Furthermore, discuss regulation anti-cancer drugs genetic well role these factors therapy response

Language: Английский

Citations

81
Transbronchial needle aspiration combined with cryobiopsy in the diagnosis of mediastinal diseases: a multicentre, open-label, randomised trial DOI
Ye Fan, Anmei Zhang, Xianli Wu

et al.

The Lancet Respiratory Medicine, Journal Year: 2022, Volume and Issue: 11(3), P. 256 - 264

Published: Oct. 22, 2022

Language: Английский

Citations

76
Treatment outcome of atypical EGFR mutations in the German National Network Genomic Medicine Lung Cancer (nNGM) DOI Creative Commons
Melanie Janning,

Juliane Süptitz,

Corinna Albers

et al.

Annals of Oncology, Journal Year: 2022, Volume and Issue: 33(6), P. 602 - 615

Published: March 7, 2022

Atypical EGFR mutations occur in 10%-30% of non-small-cell lung cancer (NSCLC) patients with and their sensitivity to classical epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) is highly heterogeneous. Patients harboring one group uncommon, recurrent (G719X, S768I, L861Q) respond EGFR-TKI. Exon 20 insertions are mostly insensitive EGFR-TKI but display exon inhibitors. Clinical outcome data very rare point compound upon systemic treatments still sparse date.In this retrospective, multicenter study the national Network Genomic Medicine (nNGM) Germany, 856 NSCLC cases atypical including co-occurring were reported from 12 centers. follow-up after treatment different EGFR-TKIs, chemotherapy immune checkpoint available 260 patients. Response was analyzed three major groups: (i) uncommon S7681, L861Q combinations), (ii) (iii) (very single mutations, 18 deletions, 19 insertions).Our comprises largest thus far real-world cohort treated treatments. We validated higher efficacy comparison 1 (uncommon), while most (group 2) not responsive. In addition, we found TKI 3) complex containing deletions or L858R independent combination partner. Notably, responses 3 rare) Co-occurring TP53 exerted a non-significant trend for detrimental effect on EGFR-TKI-treated groups 2 1.Based our findings, propose novel nNGM classification mutations.

Language: Английский

Citations

73