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LYN expression predicts the response to dasatinib in a subpopulation of lung adenocarcinoma patients.

ABSTRACT: Therapies targeting SRC family kinases (SFKs) have shown efficacy in treating non-small cell lung cancer (NSCLC). However, recent clinical trials have found that the SFK inhibitor dasatinib is ineffective in some patient cohorts. Regardless, dasatinib treatment may benefit some NSCLC patient subgroups. Here, we investigated whether expression of LYN, a member of the SFK family, is associated with patient survival, the efficacy of dasatinib, and/or NSCLC cell viability. LYN expression was associated with poor overall survival in a multivariate analysis, and this association was strongest in non-smoker female patients with adenocarcinoma (ADC). In lung ADC cells, LYN expression enhanced cell proliferation, migration, and invasion. Dasatinib inhibited LYN activity and decreased cell viability in LYN-positive ADC cell lines and xenografts. Additionally, we identified the SFKs SRC and YES as candidate dasatinib targets in LYN-negative ADC cell lines. Our findings suggest that LYN is a useful prognostic marker and a selective target of dasatinib therapy in the lung ADC subpopulation especially in female non-smokers with lung ADC.

SUBMITTER: Kim YJ

PROVIDER: S-EPMC5347739 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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LYN expression predicts the response to dasatinib in a subpopulation of lung adenocarcinoma patients.

Kim Yu Jin YJ Hong Sungyoul S Sung Minjung M Park Min Jeong MJ Jung Kyungsoo K Noh Ka-Won KW Oh Doo-Yi DY Lee Mi-Sook MS Oh Ensel E Shin Young Kee YK Choi Yoon-La YL

Oncotarget 20161201 50

Therapies targeting SRC family kinases (SFKs) have shown efficacy in treating non-small cell lung cancer (NSCLC). However, recent clinical trials have found that the SFK inhibitor dasatinib is ineffective in some patient cohorts. Regardless, dasatinib treatment may benefit some NSCLC patient subgroups. Here, we investigated whether expression of LYN, a member of the SFK family, is associated with patient survival, the efficacy of dasatinib, and/or NSCLC cell viability. LYN expression was associa ...[more]

PMID: 27756880

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Project description:BackgroundLung adenocarcinoma (LUAD) is the most common type of non-small cell lung cancer (NSCLC) with poor survival in advanced stage. Nowadays the rate of nonsmoking patients has dramatically increased and may be associated with the presence of driver mutations. Better understanding of the mutation profile data of nonsmoking LUAD patients are critical to predict survival and provide greater benefits to more patients. The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like (APOBEC) has been shown to play an important role in molecular tumorigenesis of NSCLC. However, the clinical relevance of APOBEC in nonsmoking LUAD remains to be understood.MethodsLUAD patients with somatic mutation and RNA sequencing data obtained from The Cancer Genome Atlas (TCGA) were assessed and screened in the Gene Expression Omnibus. Transcriptome data and mutational signatures were analyzed using R package. Then, we used the least absolute shrinkage and selection operator (LASSO) regression model to construct the APOBEC3 score (APOBEC3 score) model. The prognostic value was evaluated using Kaplan-Meier analysis. Finally, the functional enrichment analysis of differential expressed genes (DEGs) and the immune-related features were also estimated using R package.ResultsBy analyzing the mutational profile data of NSCLC in the TCGA database, we found that different mutation patterns existed between smoking and nonsmoking patients, and the APOBEC3 family played an important role in the mutation pattern of nonsmoking patients with LUAD. We established an APOBEC3 score and found that TCW (W = A or T) mutation counts were significantly greater in the high APOBEC3 score group than in the low APOBEC3 score group. Furthermore, there were different immune feathers and prognostic values between the high and low APOBEC3 score patients, suggesting an independent prognostic factor of APOBEC3 in nonsmoking LUAD patients.ConclusionsWe established a comprehensive view of APOBEC3 mutations in nonsmoking LUAD patients. Our review provides new insights into using the APOBEC3 mutation to predict prognosis and improve the immunotherapy response for future applications.

Project description:BackgroundInositol Polyphosphate-5-Phosphatase B (INPP5B), a inositol 5-phosphatase, plays an important role in many biological processes through phosphorylating PI(4,5)P2 and/or PI(3,4,5)P3 at the 5-position. Nevertheless, little is known about its function and cellular pathways in tumors. This study aims to investigate the potential role of INPP5B as a diagnostic and prognostic biomarker for lung adenocarcinoma (LUAD), as well as its biological functions and molecular mechanisms in LUAD.MethodsTCGA, GEO, CTPAC, and HPA datasets were used for differential expression analysis and pathological stratification comparison. The prognostic and diagnostic role of INPP5B was determined by Kaplan-Meier curves, univariate and multivariate Cox regression analysis, and receiver operating characteristics (ROC) curve analyses. The potential mechanism of INPP5B was explored through GO, KEGG, and GSEA enrichment analysis, as well as GeneMANIA and STRING protein-protein interaction (PPI) network. PicTar, PITA, and miRmap databases were used for exploring miRNA targeting INPP5B. In molecular biology experiments, immunohistochemical analyses and Western blot analyses were used to determine protein expression. Co-immunoprecipitation assay was used to detect protein-protein interactions. CCK8 assays and colony formation assays were used for the measurement of cell proliferation. Cell cycle was assessed by PI staining with flow cytometry. Cell migration was performed by Transwell assays and wound healing assays.ResultINPP5B was decreased in LUAD tissues compared with normal adjacent tissues. And the low expression of INPP5B was associated with late-stage pathological features. In addition, INPP5B was found to be a significant independent prognostic and diagnostic factor for LUAD patients. Hsa-miR-582-5p was predicted as a negative regulator of INPP5B mRNA expression. INPP5B was significantly correlated with the expression of PTEN and the activity of PI3K/AKT signaling pathways, as determined by enrichment analysis and PPI network. In vitro experiments partially confirmed the aforementioned findings. INPP5B could interact directly with PTEN. INPP5B overexpression inhibited LUAD cell proliferation and migration while downregulating the AKT pathway.ConclusionOur results demonstrated that INPP5B could inhibit the proliferation and metastasis of LUAD cells. It could serve as a novel diagnostic and prognostic biomarker for LUAD patients. Trial registration LUAD tissues and corresponding para-cancerous tissues were collected from 10 different LUAD patients at Hangzhou First People's Hospital. The Ethics Committee of Hangzhou First People's Hospital has approved this study. (registration number: IIT-20210907-0031-01; registration date: 2021.09.13).

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LYN expression predicts the response to dasatinib in a subpopulation of lung adenocarcinoma patients.

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LYN expression predicts the response to dasatinib in a subpopulation of lung adenocarcinoma patients.

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