Dataset Information

Integrated Transcriptome Analysis Reveals KLK5 and L1CAM Predict Response to Anlotinib in NSCLC at 3rd Line.

ABSTRACT: The oral multi-targeted tyrosine kinase inhibitor (TKI) anlotinib is effective for non-small cell lung cancer (NSCLC) in clinical trials at 3rd line. However, a fraction of patients remains non-responsive, raising the need of how to identify anlotinib-responsive patients. In the present study, we aimed to screen potential biomarkers for anlotinib-responsive stratification via integrated transcriptome analysis. Comparing with the anlotinib-sensitive lung cancer cell NCI-H1975, we found 1,315 genes were differentially expressed in anlotinib-resistant NCI-H1975 cells. Among the enriched angiogenesis-related genes, we observed high expression of KLK5 and L1CAM was mostly associated with poor clinical outcomes in NSCLC patients through Kaplan-Meier survival analysis in a TCGA cohort. Moreover, an independent validation in a cohort of ALTER0303 (NCT02388919) indicated that high serum levels of KLK5 and L1CAM were also associated with poor anlotinib response in NSCLC patients at 3rd line. Lastly, we demonstrated that knockdown of KLK5 and L1CAM increases anlotinib-induced cytotoxicity in anlotinib-resistant NCI-H1975 cells. Collectively, our study suggested serum levels of KLK5 and L1CAM potentially serve as biomarkers for anlotinib-responsive stratification in NSCLC patients at 3rd line.

SUBMITTER: Lu J

PROVIDER: S-EPMC6749025 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Integrated Transcriptome Analysis Reveals KLK5 and L1CAM Predict Response to Anlotinib in NSCLC at 3rd Line.

Lu Jun J Shi Qin Q Zhang Lele L Wu Jun J Lou Yuqing Y Qian Jie J Zhang Bo B Wang Shuyuan S Wang Huimin H Zhao Xiaodong X Han Baohui B

Frontiers in oncology 20190911

The oral multi-targeted tyrosine kinase inhibitor (TKI) anlotinib is effective for non-small cell lung cancer (NSCLC) in clinical trials at 3rd line. However, a fraction of patients remains non-responsive, raising the need of how to identify anlotinib-responsive patients. In the present study, we aimed to screen potential biomarkers for anlotinib-responsive stratification via integrated transcriptome analysis. Comparing with the anlotinib-sensitive lung cancer cell NCI-H1975, we found 1,315 gene ...[more]

PMID: 31572680

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Project description:ObjectiveAnlotinib hydrochloride is a multitarget tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor, fibroblast growth factor receptor, platelet-derived growth factor receptor, c-Kit, and c-MET; therefore, it exhibits both antitumor and anti-angiogenetic activities. A phase III trial has shown that anlotinib improved progression-free survival (PFS) and overall survival (OS) in patients with advanced non-small cell lung cancer (NSCLC), who presented with progressive disease or intolerance after standard chemotherapy. This study aimed to analyze the characteristics of patients receiving anlotinib treatment to determine the dominant populations who are fit for the treatment.MethodsData were collected from March 2015 to January 2017 from a randomized, double-blind, placebo-controlled, multicenter, phase III trial of anlotinib (ALTER0303). A total of 437 patients were enrolled and randomly allocated (2:1) to the anlotinib and placebo groups. Kaplan-Meier analysis and log-rank test were performed to compare PFS and OS. Cox proportional hazards model was adopted for multivariate prognostic analysis.ResultsMultivariate analysis indicated that high post-therapeutic peripheral blood granulocyte/lymphocyte ratio and elevated alkaline phosphatase levels were independent risk factors for PFS. Meanwhile, elevated thyroid-stimulating hormone, blood glucose, and triglyceride levels; hypertension; and hand-foot syndrome were independent protective factors of PFS. High post-therapeutic peripheral blood granulocyte/lymphocyte ratio, an Eastern Cooperative Oncology Group (ECOG) score ≥ 2, and the sum of the maximal target lesion length at baseline were independent risk factors of OS, and hypertriglyceridemia was an independent protective factor of OS.ConclusionsThis study preliminarily explored the possible factors that affected PFS and OS after anlotinib treatment in patients with advanced refractory NSCLC, and the baseline characteristics of the therapeutically dominant populations were then identified.

Dataset Information

Integrated Transcriptome Analysis Reveals KLK5 and L1CAM Predict Response to Anlotinib in NSCLC at 3rd Line.

Publications

Integrated Transcriptome Analysis Reveals KLK5 and L1CAM Predict Response to Anlotinib in NSCLC at 3rd Line.

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