Whole-exome sequencing on circulating tumor cells explores platinum-based chemotherapy resistance in advanced non-small cell lung cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21021-e21021
Author(s):  
Rong Li ◽  
Shuangxiu Wu ◽  
Yuanyuan Chang ◽  
Yin Wang ◽  
Boyi Li
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Genetic Information ◽  
Chemotherapy Resistance ◽  
Gene Mutations ◽  
Small Cell ◽  
Small Cell Lung ◽  
Whole Exome ◽  
Platinum Based Chemotherapy ◽  
Nsclc Patients

e21021 Background: Circulating tumour cells (CTCs) have important applications in clinical practice on early tumour diagnosis, prognostic prediction and treatment evaluation. Platinum-based chemotherapy is the first-line treatment for non-small cell lung cancer (NSCLC) patients without targeted drugs. But most patients progressed after a period of treatment. Therefore, to dissect the genetic information contributing to drug resistance and tumour progression in CTCs is valuable for guidance of treatment adjustment. Methods: In this study, we enrolled 9 NSCLC patients treated with platinum-based chemotherapy. For each patient, 10 CTCs were isolated after progression to perform a single cell-level whole-exome sequencing (WES). Meanwhile the patients’ paired primary-diagnosed FFPE sample and progressive biopsy specimens were also performed WES. Results: Comparisons of WES data between primary and progressive specimens, as well as CTCs revealed that more than half patients’ tumour mutation burden (TMB) increased after progression. Dozes to hundreds of single-nucleotide variants (SNVs) and insertions or deletions (Indels) were detected in the CTCs. Slightly more proportion of SNVs/Indels in CTCs shared with paired primary tumours (1.2%-23.1%) than with progressive samples (0.6%-11.7%). Conclusions: Functional annotation on SNVs/Indels showed that CTCs not only harboured cancer driver gene mutations, such as EGFR and TP53, shared with primary and/or progressive tumours, but also harboured chemotherapy-resistance and stem cell-related gene mutations, including SHKBP1, NUMA1, ZNF143, MUC16, ORC1, PON1, PELP1, etc. which have crucial roles in drug resistance and poor prognosis for NSCLCs. Thus, detection of genetic information in CTCs was necessary for guidance of individual therapy and drug resistance study.

scholarly journals Whole-Exome Sequencing on Circulating Tumor Cells Explores Platinum-Drug Resistance Mutations in Advanced Non-small Cell Lung Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Yuanyuan Chang ◽  
Yin Wang ◽  
Boyi Li ◽  
Xingzhong Lu ◽  
Ruiru Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Tumor Cells ◽  
Genetic Information ◽  
Gene Mutations ◽  
Small Cell ◽  
Small Cell Lung ◽  
Whole Exome ◽  
Platinum Based Chemotherapy ◽  
Nsclc Patients

Circulating tumor cells (CTCs) have important applications in clinical practice on early tumor diagnosis, prognostic prediction, and treatment evaluation. Platinum-based chemotherapy is a fundamental treatment for non-small cell lung cancer (NSCLC) patients who are not suitable for targeted drug therapies. However, most patients progressed after a period of treatment. Therefore, revealing the genetic information contributing to drug resistance and tumor metastasis in CTCs is valuable for treatment adjustment. In this study, we enrolled nine NSCLC patients with platinum-based chemotherapy resistance. For each patient, 10 CTCs were isolated when progression occurred to perform single cell–level whole-exome sequencing (WES). Meanwhile the patients’ paired primary-diagnosed formalin-fixed and paraffin-embedded samples and progressive biopsy specimens were also selected to perform WES. Comparisons of distinct mutation profiles between primary and progressive specimens as well as CTCs reflected different evolutionary mechanisms between CTC and lymph node metastasis, embodied in a higher proportion of mutations in CTCs shared with paired progressive lung tumor and hydrothorax specimens (4.4–33.3%) than with progressive lymphatic node samples (0.6–11.8%). Functional annotation showed that CTCs not only harbored cancer-driver gene mutations, including frequent mutations of EGFR and TP53 shared with primary and/or progressive tumors, but also particularly harbored cell cycle–regulated or stem cell–related gene mutations, including SHKBP1, NUMA1, ZNF143, MUC16, ORC1, PON1, PELP1, etc., most of which derived from primary tumor samples and played crucial roles in chemo-drug resistance and metastasis for NSCLCs. Thus, detection of genetic information in CTCs is a feasible strategy for studying drug resistance and discovering new drug targets when progressive tumor specimens were unavailable.

scholarly journals m6A regulators as predictive biomarkers for chemotherapy benefit and potential therapeutic targets for overcoming chemotherapy resistance in small-cell lung cancer

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Zhihui Zhang ◽  
Chaoqi Zhang ◽  
Zhaoyang Yang ◽  
Guochao Zhang ◽  
Peng Wu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Chemotherapy Resistance ◽  
Therapeutic Targets ◽  
Small Cell ◽  
Clinicopathological Parameters ◽  
Small Cell Lung ◽  
Platinum Based Chemotherapy

AbstractSmall-cell lung cancer (SCLC) is a devastating subtype of lung cancer with few therapeutic options. Despite the advent of immunotherapy, platinum-based chemotherapy is still the irreplaceable first-line therapy for SCLCs. However, drug resistance will invariably occur in most patients and the outcomes are heterogeneous. Therefore, clinically feasible classification strategies and potential therapeutic targets for overcoming chemotherapy resistance are urgently needed. N6-methyladenosine (m6A) is a novel epigenetic decisive factor that is involved in tumor progression and drug resistance. However, almost nothing is known about m6A modification in SCLC. Here, we assessed 200 SCLC samples from patients who underwent chemotherapy from three different cohorts, including a validation cohort containing 71 cases with qPCR data and an independent cohort containing 79 cases with immunohistochemistry data (quantified as H-score). We systematically characterized the predictive landscape of m6A regulators in SCLC patients following with chemotherapy. Using the LASSO Cox model, we built a seven-regulator-based (ZCCHC4, IGF2BP3, ALKBH5, YTHDF3, METTL5, G3BP1, and RBMX) chemotherapy benefit predictive classifier (m6A score) and subsequently validated the classifier in two other cohorts. Time-dependent ROC and C-index analyses showed that the m6A score to possessed superior predictive power for chemotherapy benefit in comparison with other clinicopathological parameters. A multicohort multivariate analysis revealed that the m6A score is an independent factor that affects survival benefit across multiple cohorts. Our in vitro experimental results revealed that three regulators—ZCCHC4, G3BP1, and RBMX—may serve as promising novel therapeutic targets for overcoming chemoresistance in SCLCs. Our results, for the first time, demonstrate the predictive significance of m6A regulators for chemotherapy benefit, as well as their potential as therapeutic targets for overcoming chemotherapy resistance in SCLC patients. The m6A score was found to be a reliable prognostic tool that may help guide chemotherapy decisions for patients with SCLC.

scholarly journals Small cell lung cancer transformation during antitumor therapies: A systematic review

Open Medicine ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. 1160-1167
Author(s):  
Xing Chai ◽  
Xinru Zhang ◽  
Wenqian Li ◽  
Jin Chai
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Treatment Strategies ◽  
Small Cell ◽  
Small Cell Lung ◽  
Lung Cancers ◽  
Histological Transformation ◽  
Nsclc Patients

Abstract Lung cancer is the most common cause of cancer-related death. Non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) are the two major histological categories of lung cancers. Drug resistance is a great challenge for cancer treatment, and histological transformation from NSCLC to SCLC is one of the mechanisms underlying drug resistance in NSCLC patients. SCLC-transformed patients show combined characteristics of NSCLC and SCLC; however, they lack timely diagnoses and effective treatment strategies. Thus, we reviewed the clinical characteristics of SCLC transformation patients with a literature search to enhance clinical consciousness, diagnosis, and personalized treatment for patients with it.

scholarly journals Elevated Exosome-derived Mirnas Predict Osimertinib Resistance in Non-small Cell Lung Cancer

2020 ◽  
Author(s):  
Xinying Li ◽  
Cen Chen ◽  
Zimu Wang ◽  
Jiaxin Liu ◽  
Wei Sun ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Small Cell Lung Cancer ◽  
Cell Line ◽  
Small Cell ◽  
Small Cell Lung ◽  
Expression Levels ◽  
Exosomal Mirnas ◽  
Nsclc Patients ◽  
Serum Exosomes

Abstract Background: Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations will inevitably develop drug resistance after being treated with the third-generation EGFR-tyrosine kinase inhibitor (TKI), osimertinib. In recent years, many studies have been focusing on the ability of exosomal miRNAs secreted by tumor cells to transmit resistance information. However, the mechanism of exosome-derived miRNAs in osimertinib resistance remains unexplored.Methods: We extracted and sequenced exosomes from the supernatant of the osimertinib-resistant cell line, H1975-OR, and the sensitive cell line, H1975. The results were compared with plasma exosome sequencing before and after the appearance of drug resistance in three NSCLC clinical patients treated with oral osimertinib. Exosome-derived miRNAs that had significantly increased expression levels after osimertinib resistance were screened for expanded validation in other 64 NSCLC patients.Results: Cluster analysis of the target genes revealed that exosomal miRNAs participate in osimertinib resistance mechanisms through the activation of bypass pathways (RAS-MAPK pathway abnormality and PI3K pathway activation). Exosome-derived miR-184 (p = 0.0325) and miR-3913-5p (p = 0.0169) expression levels increased significantly after the onset of osimertinib resistance. Exosomal miR-184 was correlated with lactate dehydrogenase levels (p = 0.018). Exosomal miR-3913-5p was associated with TNM stage (p = 0.045), platelet count (p = 0.024), tumor marker carcinoembryonic antigen (p = 0.045), and distant metastases (p = 0.049), especially bone metastasis (p = 0.03). In the subgroup of patients with EGFR exon 21 L858R point mutation, miR-184 (p = 0.0104) and miR-3913-5p (p = 0.0085) derived from serum exosomes had both significantly increased expression levels. In the subgroup of T790M-positive patients, miR-3913-5p derived from serum exosomes may also be a good indicator of osimertinib resistance (p = 0.013).Conclusions: The expression levels of miR-184 and miR-3913-5p derived from exosomes in the peripheral blood of NSCLC patients could be used as biomarkers to indicate osimertinib resistance.

scholarly journals Efficacy and safety of PD-1/PD-L1 inhibitors plus nab-paclitaxel for patients with non-small cell lung cancer who have progressed after platinum-based chemotherapy

2020 ◽  
Vol 12 ◽  
pp. 175883592093688
Author(s):  
Fan Zhang ◽  
Di Huang ◽  
Lei Zhao ◽  
Tao Li ◽  
Sujie Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Monotherapy Group ◽  
Small Cell Lung ◽  
Metastatic Nsclc ◽  
Platinum Based Chemotherapy ◽  
Paclitaxel Group ◽  
Nsclc Patients

Background: Immunotherapy combined with platinum-based chemotherapy is now the standard first-line treatment for non-small cell lung cancer (NSCLC) patients. However, limited evidence exists to show the efficacy of immunotherapy plus taxanes for patients who have progressed after platinum-based chemotherapy. Methods: The immunotherapy naïve patients with metastatic NSCLC who received anti-PD-1/PD-L1 monotherapy or combined with nab-paclitaxel after prior platinum-based chemotherapy from 2015 to 2018 in PLA General Hospital were identified. The progression-free survival, overall survival (OS), objective response rate (ORR), disease control rate (DCR) and safety were assessed. Results: Of 57 patients, 40 were treated with anti-PD-1/PD-L1 monotherapy and 17 were treated with anti-PD-1/PD-L1 plus nab-paclitaxel. With a median OS follow-up of 16.3 months, the nab-paclitaxel group showed significantly longer OS compared with the immune monotherapy group (median, 28.6 months versus 15.9 months, log-rank p = 0.020). When adjusted by covariates in COX proportional regression model, both the treatment group [ p = 0.009, hazard ratio (HR) 0.361; 95% confidence interval (CI) 0.168–0.773] and performance status ( p = 0.003, HR 0.372; 95% CI 0.192–0.721) demonstrated independent association with the longer OS from combination therapy. In addition, ORR was 23.5% (4/17) in the immune checkpoints inhibitors (ICIs) plus nab-paclitaxel group versus 13.5% (5/37) in immune monotherapy group ( p = 0.439), with a DCR of 88.2% (15/17) and 59.5% (22/37) ( p = 0.034), respectively. The incidence of grade 3/4 adverse events was 23.5% (4/17) in the combination group and 2.5% (1/40) in the immune monotherapy group. Conclusion: PD-1/PD-L1 inhibitor plus nab-paclitaxel resulted in significantly longer OS and higher response versus ICI single agent in metastatic NSCLC patients who have progressed after platinum-based chemotherapy. These findings need to be further explored by prospective studies.

14-3-3σ Methylation in Pretreatment Serum Circulating DNA of Cisplatin-Plus-Gemcitabine-Treated Advanced Non–Small-Cell Lung Cancer Patients Predicts Survival: The Spanish Lung Cancer Group

2005 ◽  
Vol 23 (36) ◽  
pp. 9105-9112 ◽  
Author(s):  
José Luis Ramirez ◽  
Rafael Rosell ◽  
Miquel Taron ◽  
Maria Sanchez-Ronco ◽  
Vicente Alberola ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Median Survival ◽  
Methylation Status ◽  
Small Cell ◽  
Small Cell Lung ◽  
Positive Group ◽  
Platinum Based Chemotherapy ◽  
Nsclc Patients ◽  
Pretreatment Serum

Purpose Survival in patients with advanced non–small-cell lung cancer (NSCLC) who are treated with platinum-based chemotherapy is rather variable. Methylation-dependent transcriptional silencing of 14-3-3σ, a major G2-M checkpoint control gene, could be a predictor of longer survival. Patients and Methods A sensitive methylation-specific polymerase chain reaction assay was used to evaluate 14-3-3σ methylation status in pretreatment serum DNA obtained from 115 cisplatin-plus-gemcitabine–treated advanced NSCLC patients. Results 14-3-3σ methylation was observed in all histologic types of 39 patients (34%). After a median follow-up of 9.8 months, median survival was significantly longer in the methylation-positive group (15.1 v 9.8 months; P = .004). Median time to progression was 8 months in the methylation-positive group and 6.3 months in the methylation-negative group (log-rank test, P = .027). A multivariate Cox regression model identified only 14-3-3σ methylation status and Eastern Cooperative Oncology Group performance status as independent prognostic factors for survival. In an exploratory analysis, median survival for 22 methylation-positive responders has not been reached, whereas survival was 11.3 months for 29 methylation-negative responders (P = .001). Conclusion Methylation of 14-3-3σ is a new independent prognostic factor for survival in NSCLC patients receiving platinum-based chemotherapy. It can be reliably and conveniently detected in the serum, thus obviating the need for tumor tissue analysis.

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