Translational lung cancer research最新文献

{"title":"Clinical application of minimal residual disease detection by ctDNA testing in non-small cell lung cancer: a narrative review.","authors":"Yishan Wang, Wenjun Shao, Hui Li, Peiyan Zhao, Lin Tian, Liang Zhang, Shaowei Lan, Rui Zhong, Shuang Zhang, Ying Cheng","doi":"10.21037/tlcr-24-942","DOIUrl":"https://doi.org/10.21037/tlcr-24-942","url":null,"abstract":"<p><strong>Background and objective: </strong>In recent years, significant advancements have been achieved in the treatment of non-small cell lung cancer (NSCLC), leading to prolonged patient survival; however, a subset of NSCLC patients may experience recurrence or distant metastasis following initial successful treatment. This phenomenon may be attributed to the presence of minimal residual disease (MRD) that remains undetectable by conventional imaging or laboratory techniques post-treatment. The potential sources of tumor recurrence (MRD), are significantly associated with adverse patient prognosis; therefore, the monitoring of these lesions is critically important in the management of NSCLC. This review seeks to examine the current evidence regarding the application of MRD in NSCLC clinical practice, as well as the challenges encountered in its role as a biomarker.</p><p><strong>Methods: </strong>We performed a narrative review by systematically searching the PubMed and Web of Science databases for pertinent literature published from 2005 to 2024, with the objective of identifying significant literature related to clinical research and detection techniques for MRD in NSCLC.</p><p><strong>Key content and findings: </strong>The detection of circulating tumor DNA (ctDNA) for MRD has emerged as a significant focus in high-sensitivity genetic testing for monitoring NSCLC. This method may facilitate the assessment of recurrence risk in NSCLC and inform clinical decision-making to identify high-risk patients who are likely to benefit from treatment, thereby providing a rationale for treatment escalation or de-escalation. Nevertheless, the clinical application of ctDNA MRD continues to encounter several challenges, among which improving detection sensitivity and selecting the best detection timing are urgent issues that need to be addressed.</p><p><strong>Conclusions: </strong>ctDNA MRD testing offers robust evidence to assist clinicians in the early identification of NSCLC recurrence and in guiding clinical treatment. We recommend integrating ctDNA MRD with traditional biomarkers and imaging modalities for a comprehensive evaluation aiming at optimizing treatment strategies.</p>","PeriodicalId":23271,"journal":{"name":"Translational lung cancer research","volume":"14 3","pages":"1007-1020"},"PeriodicalIF":4.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12000943/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144020193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prognostic significance of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in second-line immunotherapy for patients with non-small cell lung cancer.","authors":"Magdalena Knetki-Wróblewska, Aleksandra Grzywna, Paweł Krawczyk, Kamila Wojas-Krawczyk, Izabela Chmielewska, Tomasz Jankowski, Janusz Milanowski, Maciej Krzakowski","doi":"10.21037/tlcr-24-675","DOIUrl":"https://doi.org/10.21037/tlcr-24-675","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint inhibitors remain a therapeutic option for chemotherapy pretreated patients with advanced non-small cell lung cancer (NSCLC). Given the lack of biomarkers, there is a need to look for predictive factors in this population. Inflammatory markers derived from peripheral blood cells (PBCs) may be a valuable diagnostic tool to assess the likelihood of clinical benefit. The aim of the study was to evaluate the efficacy of the treatment and to analyse the NLR and PLR predictive values.</p><p><strong>Methods: </strong>Patients eligible for nivolumab or atezolizumab treatment in routine practice in two cancer centres between 2018 and 2021 were retrospectively analysed. Good performance status (ECOG 0-1), absence of <i>EGFR, ALK, ROS1</i> alterations and no previous immune checkpoint inhibitors treatment were the inclusion criteria. The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were calculated based on the results obtained before the start of immunotherapy. The median value was used as the cut-off point for comparative analyses.</p><p><strong>Results: </strong>The group of 332 patients was enrolled, 73.5% patients were in stage IV. The median NLR in the study group was 3.86±4.9 and the median PLR was 193.24±172.87. In the entire study group the disease control rate was 59 %, median PFS was 3.3 months [95% confidence interval (CI): 3.77 to 4.4], while median OS 11.57 months (95% CI: 9.03 to 12.73). In a univariate analysis the baseline values of NLR and PLR had a significant impact on survival, while age, gender, programmed death ligand 1 (PD-L1) expression, or type of treatment were not significant. In the multivariate Cox logistic regression model, a high value of NLR was the only factor that increased the risk of death [hazard ratio (HR) =1.6315, 95% CI: 1.2836 to 2.0737, P<0.001].</p><p><strong>Conclusions: </strong>Inflammatory indices derived from peripheral blood cells-NLR and PLR-can help assess the prognosis of patients receiving immunotherapy. They also appear to be independent prognostic factors with regard to for PFS and OS.</p>","PeriodicalId":23271,"journal":{"name":"Translational lung cancer research","volume":"14 3","pages":"749-760"},"PeriodicalIF":4.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12000957/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144020194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>ANKRD11</i> as a potential biomarker for brain metastasis from lung adenocarcinoma via cerebrospinal fluid liquid biopsy.","authors":"Qinhong Sun, Peng Xing, Qinglin Wang, Zhijun Xia, Jianyu Li, Zhitong Li, Fancheng Meng, Tongyan Liu, Siwei Wang, Rong Yin","doi":"10.21037/tlcr-24-800","DOIUrl":"https://doi.org/10.21037/tlcr-24-800","url":null,"abstract":"<p><strong>Background: </strong>Brain metastasis (BM) explains the majority of lung cancer-related mortality, especially lung adenocarcinoma (LUAD). The extensive clinical adoption of liquid biopsy presents a minimally invasive approach for the early detection and treatment management of brain metastasis from lung adenocarcinoma (BM-LUAD). Nonetheless, biomarkers for assessing BM-LUAD remain insufficient. This study aims to reveal novel biomarkers for BM-LUAD through the liquid biopsy of cerebrospinal fluid (CSF).</p><p><strong>Methods: </strong>Circulating tumor DNA (ctDNA)-based panel sequencing was conducted on CSF samples from seven patients with BM-LUAD. Additionally, single-cell RNA sequencing (scRNA-seq) data from normal lung tissue, primary tumors, and BMs were analyzed using publicly available datasets. Functional assays were performed on cell lines, complemented by <i>in vivo</i> studies in nude mice.</p><p><strong>Results: </strong>CSF liquid biopsy identified high-frequency mutations in <i>EGFR, BRCA2</i>, and <i>ANKRD11</i> among patients with BM-LUAD. Further analysis highlighted <i>ANKRD11</i> as a potential biomarker, showing reduced expression in tumor tissues and significant prognostic implications. ScRNA-seq revealed a progressive decrease in <i>ANKRD11</i> expression along tumor progression, while <i>in vitro</i> and <i>in vivo</i> assays confirmed its role in suppressing tumor invasion and metastasis.</p><p><strong>Conclusions: </strong>Our study highlights the potential of ctDNA-based CSF liquid biopsy in identifying BM-LUAD, and the efficacy in revealing novel biomarkers for BM-LUAD. Data analyses and functional assays indicated <i>ANKRD11</i> as a predictive biomarker for BM-LUAD. This result addresses, to some extent, the existing gap in biomarkers for BM-LUAD.</p>","PeriodicalId":23271,"journal":{"name":"Translational lung cancer research","volume":"14 3","pages":"662-676"},"PeriodicalIF":4.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12000962/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144036279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nomogram based on computed tomography radiomics features and clinicopathological factors to predict the prognosis of patients with non-small cell lung cancer receiving immune checkpoint inhibitor rechallenge.","authors":"Junfeng Zhao, Ying Li, Ruyue Li, Xiujing Yao, Xue Dong, Lin Su, Yintao Li","doi":"10.21037/tlcr-24-876","DOIUrl":"https://doi.org/10.21037/tlcr-24-876","url":null,"abstract":"<p><strong>Background: </strong>Whether patients with advanced non-small cell lung cancer (NSCLC) who experience progressive disease (PD) after the initial immunotherapy treatment benefit from subsequent immunotherapy remains unclear. In this study, we aimed to identify predictive factors and develop a nomogram to predict successful immunotherapy rechallenge for such patients with NSCLC to guide clinical treatment and improve prognosis.</p><p><strong>Methods: </strong>Between January 2019 and December 2022, 352 patients with advanced NSCLC who received immunotherapy rechallenge after experiencing PD were divided into the training (n=246) and validation (n=106) cohorts. Clinicopathological factors and radiomics features were included in the univariate and multivariate analyses, with significant predictive factors being used to develop the nomogram.</p><p><strong>Results: </strong>Univariate and multivariate analyses showed that time from the initial immunotherapy to PD occurrence (duration), clinical N stage, liver metastasis, treatment after PD following the first immunotherapy (post-PD treatment), and radiomics features were independent predictive factors for progression-free survival (PFS). In addition, age, duration, clinical N stage, post-PD treatment, and radiomics were independent predictive factors for overall survival (OS). Accordingly, these predictive factors were used to develop a nomogram. The area under the curves (AUCs) of the nomogram for predicting 6-, 12-, and 18-month PFS and 12-, 18-, and 24-month OS were 0.731, 0.809, 0.878, 0.742, 0.782, and 0.868, respectively, in the training cohorts, whereas the corresponding values in the validation cohort were 0.672, 0.774, 0.826, 0.833, 0.705, and 0.762. This indicated good discrimination.</p><p><strong>Conclusions: </strong>We developed and validated a predictive nomogram based on clinicopathological factors and radiomics features for the prognosis of patients with advanced NSCLC who received immunotherapy rechallenge following PD after the first immunotherapy. The nomogram showed strong predictive utility and can be a suitable tool for such patients with advanced NSCLC.</p>","PeriodicalId":23271,"journal":{"name":"Translational lung cancer research","volume":"14 3","pages":"842-856"},"PeriodicalIF":4.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12000940/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144047936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diagnostic utility of bronchoscopy for newly emerging peripheral pulmonary lesions after pulmonary resection.","authors":"Takahiro Suzuki, Yuji Matsumoto, Hideaki Furuse, Keigo Uchimura, Tatsuya Imabayashi, Takaaki Tsuchida","doi":"10.21037/tlcr-24-948","DOIUrl":"https://doi.org/10.21037/tlcr-24-948","url":null,"abstract":"<p><strong>Background: </strong>Accurate diagnosis of newly emerging peripheral pulmonary lesions (PPLs) after pulmonary resection for malignancies is essential for a favorable prognosis. We aimed to investigate the diagnostic utility and safety of bronchoscopy for PPLs after pulmonary resection of malignant tumors and to evaluate the effect of prior surgery on the diagnostic performance.</p><p><strong>Methods: </strong>As a single-center retrospective study, consecutive patients who underwent radial endobronchial ultrasound (R-EBUS)-guided transbronchial biopsy under X-ray fluoroscopic support for PPLs that developed after pulmonary resection of malignancies at National Cancer Center Hospital, Tokyo, Japan between January 2017 and December 2022 were analyzed. Because surgery was considered to influence the architecture of the ipsilateral peripheral bronchi, the diagnostic results were compared between the groups of patients after ipsilateral and contralateral pulmonary resections.</p><p><strong>Results: </strong>In total, 220 patients, 110 each in the ipsilateral and contralateral biopsy groups were analyzed. The overall number of diagnostic cases was 158 of 220 (71.8%), and the diagnostic yield was significantly lower in the ipsilateral biopsy group than in the contralateral biopsy group (62.7% <i>vs.</i> 80.9%, P=0.004). According to the lobe-specific comparisons, the middle lobe/lingula showed a significant difference in diagnostic yield between the ipsilateral and contralateral biopsy groups (45.8% <i>vs.</i> 85.7%, P=0.02). In multivariable analysis, in addition to the negative bronchus sign, not visible on radiography, and the lesion lobe (others against the right upper lobe/left upper segment), the ipsilateral biopsy group was significantly associated with a lower diagnostic yield (adjusted odds ratio, 0.41; 95% confidence interval: 0.21-0.79; P=0.008). A total of seven patients (3.2%) experienced some complications, none of which were life-threatening.</p><p><strong>Conclusions: </strong>Bronchoscopy had a sufficient diagnostic yield and safety for PPLs after pulmonary resection of malignancies. However, the diagnostic performance was reduced in biopsies ipsilateral to prior resections.</p>","PeriodicalId":23271,"journal":{"name":"Translational lung cancer research","volume":"14 3","pages":"798-809"},"PeriodicalIF":4.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12000939/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144041286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Closer proximity of pre-treatment CD4⁺ T cells to CD8⁺ T cells favor response to neoadjuvant immunotherapy in patients with PD-L1 low-expressing non-small cell lung cancer.","authors":"Liying Yang, Jiaxiao Geng, Hao Yang, Miaoqing Zhao, Hongtu Yuan, Yushan Yan, Li Wu, Fanghan Cao, Ligang Xing, Xiaorong Sun","doi":"10.21037/tlcr-24-886","DOIUrl":"https://doi.org/10.21037/tlcr-24-886","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Neoadjuvant chemo-immunotherapy improves non-small cell lung cancer (NSCLC) outcomes, but remission rates vary, emphasizing the need for biomarkers. This study aimed to investigate the impact of the baseline intratumoral CD4&lt;sup&gt;+&lt;/sup&gt; T-cell-adjacent microenvironment on the efficacy of neoadjuvant immunotherapy in NSCLC and its correlation with hypoxia-inducible factor-1α (HIF-1α), microvessel density (MVD), and cancer-associated fibroblasts (CAFs).&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Tumor samples from 49 NSCLC patients before neoadjuvant immunotherapy were retrospectively collected and subjected to multiplex immunohistochemistry staining (panel 1: DAPI/CK/CD4/CD8/CD68; Panel 2: DAPI/CK/CD4/HIF-1α/CD31/α-SMA) to characterize CD4&lt;sup&gt;+&lt;/sup&gt; T cells, CD8&lt;sup&gt;+&lt;/sup&gt; T cells CD68&lt;sup&gt;+&lt;/sup&gt; macrophages, HIF-1α&lt;sup&gt;+&lt;/sup&gt; cells, HIF-1α&lt;sup&gt;+&lt;/sup&gt;CD4&lt;sup&gt;+&lt;/sup&gt; cells, MVD, and CAF. Mann-Whitney &lt;i&gt;U&lt;/i&gt; test and receiver operating characteristic (ROC) curve were used to assess the relationship between the number and spatial distribution of each metric and the efficacy of the treatment, and Spearman's rank correlation was used to assess the correlation of each metric.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;In 49 NSCLC patients, responders (54.2%) and non-responders (45.8%). Single-indicator analysis revealed a positive correlation between high infiltration of CD8&lt;sup&gt;+&lt;/sup&gt; T cells in the stromal area and response to treatment in overall and programmed cell death-ligand 1 (PD-L1) low-expressing patients [CD8&lt;sup&gt;+&lt;/sup&gt; T (str) density: overall patient, 38 &lt;i&gt;vs.&lt;/i&gt; 16, P=0.03; tumor proportion score (TPS) 1-49% subgroup, 37 &lt;i&gt;vs.&lt;/i&gt; 14, P=0.04], with an area under curve (AUC) 0.684 and 0.746, respectively. CD4&lt;sup&gt;+&lt;/sup&gt; T cells combined with CD8&lt;sup&gt;+&lt;/sup&gt; T cells or CD68&lt;sup&gt;+&lt;/sup&gt; macrophages were analyzed and found to be more efficacious than CD4&lt;sup&gt;+&lt;/sup&gt;T&lt;sup&gt;hi&lt;/sup&gt;CD8&lt;sup&gt;+&lt;/sup&gt;T&lt;sup&gt;hi&lt;/sup&gt; compared to CD4&lt;sup&gt;+&lt;/sup&gt;T&lt;sup&gt;lo&lt;/sup&gt;CD8&lt;sup&gt;+&lt;/sup&gt;T&lt;sup&gt;lo&lt;/sup&gt; in patients with low expression of PD-L1 (P=0.03). Assessment of the nearest neighbor distance (NND) of CD4&lt;sup&gt;+&lt;/sup&gt; T cells and their adjacent cells revealed that the closer the CD4&lt;sup&gt;+&lt;/sup&gt; T cells and CD8&lt;sup&gt;+&lt;/sup&gt; T cells in the overall compartment, the better the efficacy in NSCLC patients, especially in patients with low PD-L1 expression [CD4&lt;sup&gt;+&lt;/sup&gt; T to CD8&lt;sup&gt;+&lt;/sup&gt; T (all) NND: overall patients, 34 &lt;i&gt;vs.&lt;/i&gt; 47 μm, P=0.03; TPS 1-49% subgroup, 34 &lt;i&gt;vs.&lt;/i&gt; 69 μm, P=0.006], and the AUC was 0.670 and 0.830, respectively. Notably, this favorable spatial interaction may not be dependent on direct contact between CD4&lt;sup&gt;+&lt;/sup&gt; T cells and CD8&lt;sup&gt;+&lt;/sup&gt; T cells within 10/20/30 μm (P&gt;0.05). Furthermore, in overall and PD-L1 low-expressing patients, the closer the distance between CD4&lt;sup&gt;+&lt;/sup&gt; T cells and CD8&lt;sup&gt;+&lt;/sup&gt; T cells, the higher the MVD (overall patients, r=-0.39, P=0.008; TPS 1-49% subgroup, r=-0.49, P=0.01).&lt;","PeriodicalId":23271,"journal":{"name":"Translational lung cancer research","volume":"14 3","pages":"810-823"},"PeriodicalIF":4.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12000951/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143988239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Amivantamab as a salvage therapy post-EGFR-tyrosine kinase inhibitor failure in patients with mutated EGFR non-small cell lung cancer.","authors":"Bilal Krayim, Waleed Kian, Maria Spector, Inbal Granot, Julia Dudnik, Michal Nissim, Dolev Kahala, Areen Abu Remilah, Naama R Bogot, Gleb Kornev, Noam Asna, Nir Peled, Laila C Roisman","doi":"10.21037/tlcr-24-617","DOIUrl":"https://doi.org/10.21037/tlcr-24-617","url":null,"abstract":"<p><strong>Background: </strong>Amivantamab is an approved dual epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition (MET) inhibitor for the treatment of EGFR exon 20 insertion (EGFRex20ins) mutations. Recent data support the use of amivantamab for both common and uncommon EGFR mutations after previous therapies. In this study, we investigated the role of adding amivantamab to the ongoing EGFR-tyrosine kinase inhibitor (TKI) in later lines of therapy upon progression.</p><p><strong>Methods: </strong>Patients treated at Shaare Zedek Medical Center (SZMC) from October 2021 to May 2024 who received amivantamab plus a previous EGFR-TKI. Cohort A included nine patients with common EGFR mutations [four exon 19 deletions (ex19dels), one G719C, four L858R]. Cohort B included six patients with exon 20 insertions. Safety and preliminary efficacy were evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.</p><p><strong>Results: </strong>In cohort A, the objective response rate (ORR) was 22% (L858R 50%, exon 19 0%), disease control rate (DCR) 44% (L858R 100%, exon 19 0%), median duration of treatment (mDoT) 3 months (L858R 7.5 months, exon 19 2.3 months), and median overall survival (mOS) 6.7 months (L858R 14.4 months, exon 19 4.6 months). In cohort B, ORR was 17%, DCR 83%, mDoT 5.5 months, and mOS 16.2 months. Grade ≥3 toxicities included nausea, diarrhea, rash, infusion reactions, and thromboembolism.</p><p><strong>Conclusions: </strong>This pilot study suggests that adding late-line amivantamab to an ongoing EGFR-TKI may have potential benefits in selected non-small cell lung cancer (NSCLC) patients with EGFR mutations, but resulted in high skin toxicity. Patients with EGFR L858R mutations appeared to show improved responses to amivantamab compared to the lack of response with ex19dels, while acquired resistance was associated with loss of the original EGFR driver mutation and MET alterations. However, these preliminary findings lack robust evidence due to study limitations, and larger, prospective, multi-center trials are needed to validate these results.</p>","PeriodicalId":23271,"journal":{"name":"Translational lung cancer research","volume":"14 3","pages":"707-717"},"PeriodicalIF":4.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12000964/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144020188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting of arachidonic acid-modulated autophagy to enhance the sensitivity of <i>ROS1</i> ⁺ or <i>ALK</i> ⁺ non-small cell lung cancer to crizotinib therapy.","authors":"Hui Jie, Hongjin Lai, Zihuai Wang, Min Yi, Yi Liu, Edyta Maria Urbanska, Eric Santoni-Rugiu, Shiyou Wei, Yuhao Chen, Chuan Li, Tengyong Wang, Nanzhi Luo, Lunxu Liu, Senyi Deng, Chenglin Guo","doi":"10.21037/tlcr-2025-105","DOIUrl":"https://doi.org/10.21037/tlcr-2025-105","url":null,"abstract":"<p><strong>Background: </strong>As an approved targeting drug, crizotinib has been widely used in the treatment of patients with non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase (<i>ALK</i>) rearrangements or c-ros oncogene 1 (<i>ROS1</i>) fusions and has demonstrated remarkable therapeutic effects. However, crizotinib-treated patients frequently experience drug resistance, and there are still some underlying mechanisms, which remain unclear. Autophagy, a cellular process that involves the degradation and recycling of cellular components, has been implicated in the development of drug resistance. In this study, we aim to elucidate the mechanisms of crizotinib resistance involving autophagy dysregulation and identify novel therapeutic targets to overcome this resistance.</p><p><strong>Methods: </strong>We first established a model for crizotinib resistance in HCC78 and H3122 cells. Next, the level of proliferation, apoptosis, autophagy flux, and reactive oxygen species (ROS) of these cells were measured. Subsequently, we analyzed the published single-cell RNA sequencing data from three <i>ALK</i>-rearranged lung cancer organoid samples and performed a metabolomics assay on crizotinib-resistant HCC78 cells. Finally, the therapeutic effects were confirmed <i>in vitro</i> by targeting autophagy flux.</p><p><strong>Results: </strong>Crizotinib induced cell apoptosis and growth arrest by promoting the accumulation of autophagosomes through the inhibition of autophagy flux in <i>ROS1</i> ⁺ or <i>ALK</i> ⁺ NSCLC. In contrast, crizotinib-resistant NSCLC cells showed inactivation of signal transducer and activator of transcription 3 (STAT3) phosphorylation and downregulation of prostaglandin endoperoxide synthase 2 (<i>PTGS2</i>), leading to an increase in the metabolite arachidonic acid (AA). AA further promoted autophagy flux and reduced autophagosome accumulation, driving crizotinib resistance under conditions of drug stress. Moreover, chloroquine (CQ), anti-malaria drug and lysosome inhibitor developed in 1940, could induce cell death in crizotinib-resistant NSCLC by blocking AA-mediated autophagy flux and facilitating autophagosome accumulation, significantly enhancing the treatment efficacy of crizotinib in drug-resistant NSCLC.</p><p><strong>Conclusions: </strong>We discovered a new mechanism of first generation ALK- and ROS1-TKIs resistance, which points to the role of the metabolite AA in resistance to tyrosine kinase inhibitors. It may potentially provide an alternative strategy to overcoming crizotinib resistance in NSCLC treatment by reversing AA-mediated autophagy.</p>","PeriodicalId":23271,"journal":{"name":"Translational lung cancer research","volume":"14 3","pages":"878-896"},"PeriodicalIF":4.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12000944/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144036282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Will INSPIRE crown iruplinalkib as a new standard choice in first-line advanced <i>ALK</i>-positive non-small cell lung cancer?","authors":"Blerina Resuli, Diego Kauffmann-Guerrero","doi":"10.21037/tlcr-24-655","DOIUrl":"https://doi.org/10.21037/tlcr-24-655","url":null,"abstract":"","PeriodicalId":23271,"journal":{"name":"Translational lung cancer research","volume":"14 3","pages":"653-656"},"PeriodicalIF":4.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12000941/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144061756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neoadjuvant immunochemotherapy demonstrated improved efficacy and comparable safety to neoadjuvant chemotherapy for limited-stage small-cell lung cancer: a cohort study.","authors":"Lijiang Song, Xiaowei Mao, Haichuan Hu, Hu Zhang, Xinxin Ying, Lichen Zhang, Kai Liu, Huiyong Han, Dongde Li, Zhengfu He","doi":"10.21037/tlcr-2024-1256","DOIUrl":"https://doi.org/10.21037/tlcr-2024-1256","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Small-cell lung cancer (SCLC) accounts for 10-15% of all lung cancers. Neoadjuvant therapy followed by surgery has been applied in treatment of limited-stage SCLC (LS-SCLC). The synergistic effect of neoadjuvant immunochemotherapy (NIC) has been validated in the treatment of non-small cell lung cancer (NSCLC). Therefore, we compared the safety and efficacy between NIC and neoadjuvant chemotherapy (NC) for treating LS-SCLC.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;This retrospective study included 10 patients diagnosed with LS-SCLC (stage I-IIIB) from 2019 to 2021. Five patients received NIC, while the other five received NC. Patients received two cycles of etoposide and cisplatin chemotherapy (EP) regimen (75 mg/m&lt;sup&gt;2&lt;/sup&gt; of cisplatin and 160 mg/m&lt;sup&gt;2&lt;/sup&gt; of etoposide) with or without immunotherapy (durvalumab or pembrolizumab) every 3 weeks before surgery. Imaging evaluation was performed before neoadjuvant therapy and surgery. Imaging and pathological tumor response, neoadjuvant treatment-related adverse events, perioperative information, and complications were evaluated. The follow-up data were obtained from the regular reviews in hospital and by telephone. The follow-up was terminated at December 2023 or if the patient died or experienced recurrence.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;The objective response rate (ORR) was 80% (4/5) in the NIC group and 100% (5/5) in the NC group. No patients experienced progressive disease (PD). Patients in the NIC group achieved more improvement of pulmonary function than did those in the NC group. All NIC and NC patients had R0 resection. No significant difference in surgical information was found between the two groups. One of the five patients in the NIC group experienced alveolopleural fistula, while one of the five patients in the NC group experienced respiratory failure postoperatively and died thereafter. One patient in the two groups was diagnosed with hydrothorax after tube removal. Pathological downstaging occurred in 4 patients in the NIC group and 2 patients in the NC groups. The rate of pathological complete remission (pCR) and major pathological response (MPR) was 20% and 40% in the NIC group, respectively, while in the NC group, it was 20% and 20%, respectively. In one patient with NIC, adjuvant therapy was abandoned due to hepatic insufficiency. During the period of follow-up, one patient in the NIC group experienced brain metastasis 1 year after surgery, while one patient in the NC group was diagnosed with local lymph node metastasis and distant metastasis half a year later.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;NIC might provide greater advantages in downstaging, pulmonary function improvement and pathological regression in patients with LS-SCLC than NC while providing similarly safety and surgical feasibility. These findings may help clinicians develop more individualized therapy. However, randomized controlled trials are required to further validate our findings.","PeriodicalId":23271,"journal":{"name":"Translational lung cancer research","volume":"14 3","pages":"963-974"},"PeriodicalIF":4.0,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12000953/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144060942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}