scholarly journals Identification of a targetable KRAS-mutant epithelial population in non-small cell lung cancer

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Giorgia Maroni ◽  
Mahmoud A. Bassal ◽  
Indira Krishnan ◽  
Chee Wai Fhu ◽  
Virginia Savova ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Targeted Therapy ◽  
Single Cell ◽  
Murine Model ◽  
Tumor Heterogeneity ◽  
Small Cell ◽  
Small Cell Lung ◽  
Murine Lung ◽  
Single Cell Rna Sequencing

AbstractLung cancer is the leading cause of cancer deaths. Tumor heterogeneity, which hampers development of targeted therapies, was herein deconvoluted via single cell RNA sequencing in aggressive human adenocarcinomas (carrying Kras-mutations) and comparable murine model. We identified a tumor-specific, mutant-KRAS-associated subpopulation which is conserved in both human and murine lung cancer. We previously reported a key role for the oncogene BMI-1 in adenocarcinomas. We therefore investigated the effects of in vivo PTC596 treatment, which affects BMI-1 activity, in our murine model. Post-treatment, MRI analysis showed decreased tumor size, while single cell transcriptomics concomitantly detected near complete ablation of the mutant-KRAS-associated subpopulation, signifying the presence of a pharmacologically targetable, tumor-associated subpopulation. Our findings therefore hold promise for the development of a targeted therapy for KRAS-mutant adenocarcinomas.

scholarly journals P02.05 Comprehensive profiling of tumor heterogeneity and its microenvironment in advanced non-small cell lung cancer at single cell resolution

2021 ◽  
Vol 9 (Suppl 1) ◽  
pp. A9.2-A9
Author(s):  
Y Cordts ◽  
F Wu ◽  
J Fan ◽  
M Odenthal ◽  
R Buettner ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Microenvironment ◽  
Single Cell ◽  
Tumor Heterogeneity ◽  
Cell Types ◽  
Small Cell ◽  
Small Cell Lung ◽  
Part Time ◽  
Nsclc Patients ◽  
Shed Light

BackgroundLung cancer is a highly heterogeneous disease. Cancer cells and cells within the tumor microenvironment together determine disease progression, as well as response to or escape from treatment.Materials and MethodsTo map the cell type-specific transcriptome landscape of cancer cells and their tumor microenvironment in advanced non-small cell lung cancer (NSCLC), we analyzed 42 tissue biopsy samples from stage III/IV NSCLC patients by single cell RNA sequencing and presented the large scale, single cell resolution profiles of advanced NSCLCs.ResultsIn addition to cell types described in previous single cell studies of early stage lung cancer, we were able to identify new cell types such as follicular dendritic cells and T helper 17 cells. Tumors from different patients display large heterogeneity in cellular composition, chromosomal structure, developmental trajectory, intercellular signaling network and phenotype dominance. Our study also revealed a correlation of tumor heterogeneity with tumor associated neutrophils, which might help to shed light on their function in NSCLC.ConclusionsThis study presented first-time the tumor heterogeneity and tumor microenvironment profile from late-stage, largely untreated NSCLC patients, and shed light on possible treatment regimes.Disclosure InformationY. Cordts: A. Employment (full or part-time); Modest; Singleron Biotechnologies GmbH. F. Wu: None. J. Fan: A. Employment (full or part-time); Modest; Singleron Biotechnologies GmbH. M. Odenthal: None. R. Buettner: None. C. Zhou: None.

scholarly journals Tumour-derived exosomal lncRNA-SOX2OT promotes bone metastasis of non-small cell lung cancer by targeting the miRNA-194-5p/RAC1 signalling axis in osteoclasts

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Jianjiao Ni ◽  
Xiaofei Zhang ◽  
Juan Li ◽  
Zhiqin Zheng ◽  
Junhua Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Bone Metastasis ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Osteoclast Differentiation ◽  
Small Cell ◽  
Signalling Pathway ◽  
Small Cell Lung

AbstractBone is a frequent metastatic site of non-small cell lung cancer (NSCLC), and bone metastasis (BoM) presents significant challenges for patient survival and quality of life. Osteolytic BoM is characterised by aberrant differentiation and malfunction of osteoclasts through modulation of the TGF-β/pTHrP/RANKL signalling pathway, but its upstream regulatory mechanism is unclear. In this study, we found that lncRNA-SOX2OT was highly accumulated in exosomes derived from the peripheral blood of NSCLC patients with BoM and that patients with higher expression of exosomal lncRNA-SOX2OT had significantly shorter overall survival. Additionally, exosomal lncRNA-SOX2OT derived from NSCLC cells promoted cell invasion and migration in vitro, as well as BoM in vivo. Mechanistically, we discovered that NSCLC cell-derived exosomal lncRNA-SOX2OT modulated osteoclast differentiation and stimulated BoM by targeting the miRNA-194-5p/RAC1 signalling axis and TGF-β/pTHrP/RANKL signalling pathway in osteoclasts. In conclusion, exosomal lncRNA-SOX2OT plays a crucial role in promoting BoM and may serve as a promising prognostic biomarker and treatment target in metastatic NSCLC.

scholarly journals Predicting ROR1/BCL2 combination targeted therapy of small cell carcinoma of the lung

2021 ◽  
Vol 12 (6) ◽  
Author(s):  
Walter Z. Wang ◽  
Konstantin Shilo ◽  
Joseph M. Amann ◽  
Alyssa Shulman ◽  
Mohammad Hojjat-Farsangi ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Targeted Therapy ◽  
Small Cell Lung Cancer ◽  
Cell Lines ◽  
Cell Lung Cancer ◽  
Therapeutic Target ◽  
Small Cell ◽  
Orphan Receptor ◽  
Small Cell Lung ◽  
Sclc Patient

AbstractSmall cell lung cancer (SCLC) remains a deadly form of cancer, with a 5-year survival rate of less than 10 percent, necessitating novel therapies. Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is an oncofetal protein that is emerging as a therapeutic target and is co-expressed with BCL2 in multiple tumor types due to microRNA coregulation. We hypothesize that ROR1-targeted therapy is effective in small cell lung cancer and synergizes with therapeutic BCL2 inhibition. Tissue microarrays (TMAs) and formalin-fixed paraffin-embedded (FFPE) SCLC patient samples were utilized to determine the prevalence of ROR1 and BCL2 expression in SCLC. Eight SCLC-derived cell lines were used to determine the antitumor activity of a small molecule ROR1 inhibitor (KAN0441571C) alone and in combination with the BCL2 inhibitor venetoclax. The Chou-Talalay method was utilized to determine synergy with the drug combination. ROR1 and BCL2 protein expression was identified in 93% (52/56) and 86% (48/56) of SCLC patient samples, respectively. Similarly, ROR1 and BCL2 were shown by qRT-PCR to have elevated expression in 79% (22/28) and 100% (28/28) of SCLC patient samples, respectively. KAN0441571C displayed efficacy in 8 SCLC cell lines, with an IC50 of 500 nM or less. Synergy as defined by a combination index of <1 via the Chou-Talalay method between KAN0441571C and venetoclax was demonstrated in 8 SCLC cell lines. We have shown that ROR1 inhibition is synergistic with BCL2 inhibition in SCLC models and shows promise as a novel therapeutic target in SCLC.

scholarly journals Epidermal Growth Factor Receptor Expression and Resistance Patterns to Targeted Therapy in Non-Small Cell Lung Cancer: A Review

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1206
Author(s):  
Emma-Anne Karlsen ◽  
Sam Kahler ◽  
Joan Tefay ◽  
Shannon R. Joseph ◽  
Fiona Simpson
Keyword(s):  
Lung Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Targeted Therapy ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Small Cell ◽  
Small Cell Lung ◽  
Resistance Patterns ◽  
Epidermal Growth

Globally, lung cancer is the leading cause of cancer-related death. The majority of non-small cell lung cancer (NSCLC) tumours express epidermal growth factor receptor (EGFR), which allows for precise and targeted therapy in these patients. The dysregulation of EGFR in solid epithelial cancers has two distinct mechanisms: either a kinase-activating mutation in EGFR (EGFR-mutant) and/or an overexpression of wild-type EGFR (wt-EGFR). The underlying mechanism of EGFR dysregulation influences the efficacy of anti-EGFR therapy as well as the nature of resistance patterns and secondary mutations. This review will critically analyse the mechanisms of EGFR expression in NSCLC, its relevance to currently approved targeted treatment options, and the complex nature of secondary mutations and intrinsic and acquired resistance patterns in NSCLC.

scholarly journals Docetaxel-loaded exosomes for targeting non-small cell lung cancer: preparation and evaluation in vitro and in vivo

Drug Delivery ◽  
2021 ◽  
Vol 28 (1) ◽  
pp. 1510-1523
Author(s):  
Ying Wang ◽  
Mimi Guo ◽  
Dingmei Lin ◽  
Dajun Liang ◽  
Ling Zhao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung ◽  
Preparation And Evaluation

scholarly journals Surgical choice of non-small cell lung cancer with unexpected pleural dissemination intraoperatively

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Junjie Hu ◽  
Yan Chen ◽  
Xinsheng Zhu ◽  
Qiang Ma ◽  
Jing Zhang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Targeted Therapy ◽  
Small Cell Lung Cancer ◽  
Distant Metastasis ◽  
Survival Benefit ◽  
Tumor Resection ◽  
Small Cell ◽  
Small Cell Lung ◽  
Systematic Lymphadenectomy ◽  
Cox Analysis

Abstract Background Whether patients with non-small cell lung cancer (NSCLC) with unexpected pleural dissemination (UPD) could get survival benefit from tumor resection remained controversial. Methods Totally, 169 patients with NSCLC with UPD were included between 2012 and 2016. Patients were divided into the tumor resection and open-close group. Progression-free survival (PFS) and overall survival (OS) were compared with a log-rank test. The multivariable Cox analysis was applied to identify prognostic factors. Results Sixty-five patients received open-close surgery and 104 patients underwent main tumor and visible pleural nodule resection. Tumor resection significantly prolonged OS (hazard ratio [HR]: 0.408, P < 0.001), local PFS (HR: 0.283, P < 0.001), regional PFS (HR: 0.506, P = 0.005), and distant metastasis (HR: 0.595, P = 0.032). Multivariable Cox analysis confirmed that surgical method was an independent prognostic factor for OS, local PFS and regional PFS, except distant metastasis. Subgroup analyses indicated that tumor resection could not improve OS in the patients who received targeted therapy (HR: 0.649, P = 0.382), however, tumor resection was beneficial for the patients who received adjuvant chemotherapy alone (HR: 0.322, P < 0.001). In the tumor resection group, lobectomy (HR: 0.960, P = 0.917) and systematic lymphadenectomy (HR: 1.512, P = 0.259) did not show survival benefit for OS. Conclusions Main tumor and visible pleural nodule resection could improve prognosis in patients with UPD who could not receive adjuvant targeted therapy. Sublobar resection without systematic lymphadenectomy may be the optimal procedure.

Sign in / Sign up

Export Citation Format

Share Document