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Apatinib Mesylate in the treatment of advanced progressed lung adenocarcinoma patients with EGFR-TKI resistance -A Multicenter Randomized Trial.

ABSTRACT: Few pieces of evidence have been published on the use of Apatinib Mesylate (AM) against EGFR-TKI resistance in lung adenocarcinoma (LA) patients. Here, we investigate the clinical efficacy and safety of AM in the treatment of advanced progressed epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) resistant LA patients. We conducted a double-blind, randomized controlled trial in 68 patients admitted to 18 hospitals of Anhui province in China. The efficacy and safety of AM treatment were evaluated in terms of progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR), as well as related adverse events (AE). A literature knowledge database analysis and a pathway model reconstruction were performed to decipher the relevant mechanism may be involved. Our results showed that, compared to the control group, AM presented improved efficacy in PFS (P?=?0.033), ORR (P?

SUBMITTER: Fang P

PROVIDER: S-EPMC6768876 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Apatinib Mesylate in the treatment of advanced progressed lung adenocarcinoma patients with EGFR-TKI resistance -A Multicenter Randomized Trial.

Fang Ping P Zhang Liqin L Zhang Xianru X Yu Jiawen J Sun Jun J Jiang Qi-An QA Zha Mingbao M Nesterova Anastasia P AP Cao Hongbao H

Scientific reports 20190930 1

Few pieces of evidence have been published on the use of Apatinib Mesylate (AM) against EGFR-TKI resistance in lung adenocarcinoma (LA) patients. Here, we investigate the clinical efficacy and safety of AM in the treatment of advanced progressed epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) resistant LA patients. We conducted a double-blind, randomized controlled trial in 68 patients admitted to 18 hospitals of Anhui province in China. The efficacy and safety of AM treat ...[more]

PMID: 31570733

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Project description:BACKGROUND:The resistance of lung cancer to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is one of the unconquered frontiers in chemotherapy. Mitogen-inducible gene 6 (Mig-6) is known to inhibit the kinase activity of epidermal growth factor receptor (EGFR). Similarly, numerous studies of mouse models suggested tumor suppressive function of Mig-6 in lung cancer. On the contrary, the results of clinical investigations revealed that lung cancer patients with elevated expression of Mig-6 are associated with a poor prognosis. More recent work showed that unlike wild type (WT) EGFR, mutant EGFR phosphorylates Mig-6 and phosphorylated Mig-6 negatively regulates the degradation of EGFR mutants in lung adenocarcinoma. Here, we tried to untangle the controversies surrounding Mig-6 function as a protagonist or an antagonist of EGFR-TKI resistant lung cancer. METHODS:We compared the expression and phosphorylation status of Mig-6 in the EGFR-TKI resistant lung adenocarcinoma (PC9/GR cells) to EGFR-TKI sensitive lung adenocarcinoma (PC9 cells). We investigated the function of Mig-6 by either depletion or overexpression of Mig-6 in those cells and evaluated the efficacy of combining of Mig-6 knock-down and EGFR-TKI treatment in PC9/GR. The correlation between Mig-6 expressions and the prognoses of lung adenocarcinoma was examined by The Cancer Genome Atlas (TCGA) data and clinical samples. RESULTS:Our results indicated that the expression of Mig-6 was significantly increased in PC9/GR cells compared to that of PC9 cells. The significant portion of Mig-6 existed as a phosphorylated form in PC9 and PC9/GR cells. Moreover, overexpression of Mig-6 significantly increased the cell proliferation, invasion and epithelial mesenchymal transition (EMT) in PC9 cells. Combination of Mig-6 knock-down and EGFR-TKI treatment significantly overcame the EGFR-TKI resistance of PC9/GR cells. In addition, our analyses of clinical samples confirmed that high Mig-6 expressions positively correlate with a poor prognosis and EGFR-TKI resistance in lung adenocarcinoma. CONCLUSION:Our findings reinforce scientific notion of Mig-6 as an oncoprotein in the context of EGFR-TKI resistant lung adenocarcinoma. We propose that targeting Mig-6 may be a promising strategy to overcome the EGFR-TKI resistance in lung cancer.

Project description:Objectives: Epidermal growth factor receptor-tyrosine kinase inhibitors are widely used for lung epidermal growth factor receptor-positive lung adenocarcinomas, but acquired resistance is inevitable. Although non-coding RNAs, such as circular RNA and microRNA, are known to play vital roles in epidermal growth factor receptor-tyrosine kinase inhibitor resistance, comprehensive analysis is lacking. Thus, this study aimed to explore the circular RNA-microRNA-messenger RNA regulatory network involved in epidermal growth factor receptor-tyrosine kinase inhibitor resistance. Methods: To identify differentially expressed genes between the epidermal growth factor receptor-tyrosine kinase inhibitor sensitive cell line PC9 and resistant cell line PC9/ epidermal growth factor receptor-tyrosine kinase inhibitor resistance(PC9/ER), circular RNA, microRNA and messenger RNA microarrays were performed. Candidates were then identified to construct a circular RNA-microRNA-messenger RNA network using bioinformatics. Additionally, Gene Oncology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were conducted to evaluate the network messenger RNA, setting up a protein-protein interaction network for hub-gene identification. Afterwards, RNA immunoprecipitation was performed to enrich microRNA, and quantitative real-time PCR was used to estimated gene expression levels. Results: In total, 603, 377, and 1863 differentially expressed circular RNA, microRNA, messenger RNAs, respectively, were identified using microarray analysis, constructing a circular RNA-microRNA-messenger RNA network containing 18 circular RNAs, 17 microRNAs and 175 messenger RNAs. Moreover, Gene Oncology and Kyoto Encyclopedia of Genes and Genomes pathway analyses showed that the most enriched biological process terms and pathways were related to epidermal growth factor receptor-tyrosine kinase inhibitor resistance, including Wnt and Hippo signaling pathways. Based on the competing endogenous RNA and protein-protein interaction network, circ-0007312 was showed to interact with miR-764 and both circ-0003748 and circ-0001398 were shown to interact with miR-628; both these microRNAs targeted MAPK1. Furthermore, circ-0007312, circ-0003748, circ-0001398, and MAPK1 were up-regulated, whereas miR-764 and miR-628 were downregulated in PC9/ER cells as compared to parental PC9 cells. We also found that circ-0007312 and miR-764 were positively expressed in plasma. Conclusions: Our original study associated with mechanism of target therapy in lung cancer provided a systematic and comprehensive regulation of circular RNA, microRNA and messenger RNA in epidermal growth factor receptor-tyrosine kinase inhibitor resistance. It was found that circ-0007312- miR-764-MAPK1, circ-0003748-miR-628-MAPK1, and circ-0001398-miR-628-MAPK1 axis may play key roles in epidermal growth factor receptor-tyrosine kinase inhibitor resistance.

Dataset Information

Apatinib Mesylate in the treatment of advanced progressed lung adenocarcinoma patients with EGFR-TKI resistance -A Multicenter Randomized Trial.

Publications

Apatinib Mesylate in the treatment of advanced progressed lung adenocarcinoma patients with EGFR-TKI resistance -A Multicenter Randomized Trial.

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