DNA Methylation status of Wnt antagonist SFRP5 can predict the response to the EGFR-tyrosine kinase inhibitor therapy in non-small cell lung cancer

Zhu, Jian; Wang, Yuyan; Duan, Jianchun; Bai, Hua; Wang, Zhijie; Wei, Lai; Zhao, Jun; Zhuo, Minglei; Wang, Shuhang; Yang, Lu; An, Tongtong; Wu, Meina; Wang, Jie

doi:10.1186/1756-9966-31-80

Cited by 40 publications

(32 citation statements)

References 37 publications

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“…2B and 2C). Multivariate analysis showed that Wif1 methylation exhibited a trend toward worse OS in AC patients with EGFR mutation (adjusted HR = 3.85, 95% CI = 0.79-18.72, P = 0.075) ( Table 2), being comparable with a recent observation that in ACs with EGFR mutation group, patients with methylated Wnt antagonist SFRP5 has a significantly shorter progression free survival than those with unmethylated SFRP5 (Zhu et al, 2012). Crosstalk between Wnt and EGFR signaling in cancers has been well documented (Hu et al, 2010).…”

supporting

confidence: 80%

Wif1 Hypermethylation as Unfavorable Prognosis of Non-Small Cell Lung Cancers with EGFR Mutation

Lee

Park

Kim

2013

Molecules and Cells

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Lung cancer is a leading cause of cancer-related mortality across the world and tobacco smoking is the major risk factor. The Wnt signaling pathway is known to be involved in smoke-induced tumorigenesis in the lung. Promoter hypermethylation of Wnt inhibitory factor 1 (Wif1) has become a common event in a number of human tumors. Using a methylation-specific PCR, hypermethylation of the Wif1 gene promoter was evaluated in 139 primary nonsmall cell lung cancers (NSCLCs) and its correlation with clinicopathological and prognostic parameters was evaluated. Methylation of Wif1 was observed in 47.5% and 20.9% of neoplastic and adjacent normal lung tissues, respectively. Its methylation rate tended to be higher in stage I than stages II-IIIA. Results of Kaplan-Meier analysis showed no significant difference in overall survival according to Wif1 methylation status. However, Wif1 methylation showed an association with unfavorable prognosis of adenocarcinoma (AC) patients with EGFR mutation. According to our current findings, Wif1 promoter methylation is an early, frequent event as an epigenetic field manner and could be considered as a useful prognostic marker for AC patients with EGFR mutation. Further investigation into the therapeutic potential of this finding is warranted.

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confidence: 80%

Wif1 Hypermethylation as Unfavorable Prognosis of Non-Small Cell Lung Cancers with EGFR Mutation

Lee

Park

Kim

2013

Molecules and Cells

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“…Microarray-based screen pairing of the differential genetic profile of chemosensitive and chemoresistant cell lines have been reported (16)(17)(18)(19)(20) (21). However, only few reports focused on the relationship between egfr-tKi resistance and aberrant DNA methylation (22,23). Furthermore, DNA demethylating agent, 5-azacytidine, might increase the cellular sensitivity to gefitinib and control NSCLC cell growth and apoptosis (24).…”

Section: Introductionmentioning

confidence: 99%

Long-term exposure to gefitinib induces acquired resistance through DNA methylation changes in the EGFR-mutant PC9 lung cancer cell line

Terai¹,

Soejima²,

Yasuda³

et al. 2014

International Journal of Oncology

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Abstract. this study was designed to identify epigenetically regulated genes and to clarify the contribution of epigenetic alteration to acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (egfr-tKis). We established a gefitinib-resistant lung cancer cell line, PC9, which was originally gefitinib-sensitive, by serial long-term exposure to gefitinib. RNA and DNA were collected from both gefitinib-sensitive and -resistant PC9 cells, and comprehensive DNA methylation and mRNA expression analyses were performed using Infinium HumanMethylation27 Bead Arrays and Agilent SurePrint G3 Human Gene Expression 8x60K Array, respectively. DNA methylation was increased in 640 genes in gefitinib-resistant cells compared to parental cells. Among them, we selected 29 candidate genes that presented a decrease in mRNA expression in resistant PC9. We further studied four of the selected genes (C10orf116, IGFBP3, KL, and S100P) and found that KL or S100P silencing by sirna induced a decrease in gefitinib sensitivity compared to that in the negative control in PC9. In conclusion, KL and S100P could be potential targets to overcome resistance to EGFR-TKIs.

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“…Inhibition of various components of Wnt pathway with shRNAs or small molecules significantly increased the efficacy of EGFR inhibitors both in vitro and in vivo (25). The DNA methylation status of the Wnt antagonist SFRP5 can predict the response to EGFR-TKI therapy in NSCLC (8). Wnt inhibitory factor 1 (Wif1) promoter methylation is an early and frequent event as an epigenetic field manner, and Wif1 hypermethylation can be as an unfavorable prognosis marker of NSCLC with EGFR mutation (26).…”

Section: Discussionmentioning

confidence: 99%

“…The pathway analysis of the differential methylated genes indicated that Wnt signaling pathway, Cadherin signaling pathway, and other pathways enriched in both patients are related to the EGFR pathway. Many studies have proven that Wnt signaling pathway has a role in EGFR-mutated lung cancer (8,25,26). Inhibition of various components of Wnt pathway with shRNAs or small molecules significantly increased the efficacy of EGFR inhibitors both in vitro and in vivo (25).…”

Section: Discussionmentioning

confidence: 99%

“…DNA methylation status of Wnt antagonist genes from 155 NSCLC patients who received EGFR-TKI treatment were investigated using methylation-specific PCR, showing that DNA methylation status of Wnt antagonist SFRP5 can predict the response to EGFR-TKI therapy in NSCLC, and methylated SFRP5 may contribute to shorter progression-free survival (PFS; ref. 8). The EGFR 19 deletion cell line PC-9, with the unmethylated promoter region of EGFR gene, was more sensitive to gefitinib compared with the other EGFR 19 deletion cell line H1650 with the methylated promoter region, which was "resistant" to gefitinib, suggesting that EGFR gene promoter methylation may be a potential mechanism for acquired resistance to gefitinib (9).…”

Section: Introductionmentioning

confidence: 99%

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Genome-wide DNA Methylation Analysis Reveals GABBR2 as a Novel Epigenetic Target for EGFR 19 Deletion Lung Adenocarcinoma with Induction Erlotinib Treatment

Niu

Liu

Zhou

et al. 2017

Clinical Cancer Research

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Purpose: The past decade has witnessed the rapid development of personalized targeted therapies in lung cancer. It is still unclear whether epigenetic changes are involved in the response to tyrosine kinase inhibitor (TKI) treatment in epidermal growth factor receptor (EGFR)-mutated lung cancer. Experimental Design: Methyl-sensitive cut counting sequencing (MSCC) was applied to investigate the methylation changes in paired tissues before and after erlotinib treatment for 42 days with partial response (PR) from stage IIIa (N2) lung adenocarcinoma patients (N = 2) with EGFR 19 deletion. The Sequenom EpiTYPER assay was used to validate the changed methylated candidate genes. Up- or downregulation of the candidate gene was performed to elucidate the potential mechanism in the regulation of erlotinib treatment response. Results: Sixty aberrant methylated genes were screened using MSCC sequencing. Two aberrant methylated genes, CBFA2T3 and GABBR2, were clearly validated. A same differential methylated region (DMR) between exon 2 and exon 3 of GABBR2 gene was confirmed consistently in both patients. GABBR2 was significantly downregulated in EGFR 19 deletion cells, HCC4006 and HCC827, but remained conserved in EGFR wild-type A549 cells after erlotinib treatment. Upregulation of GABBR2 expression significantly rescued erlotinib-induced apoptosis in HCC827 cells. GABBR2 was significantly downregulated, along with the reduction of S6, p-p70 S6, and p-ERK1/2, demonstrating that GABBR2 may play an important role in EGFR signaling through the ERK1/2 pathway. Conclusions: We demonstrated that GABBR2 gene might be a novel potential epigenetic treatment target with induction erlotinib treatment for stage IIIa (N2) EGFR 19 deletion lung adenocarcinoma. Clin Cancer Res; 23(17); 5003–14. ©2017 AACR.

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DNA Methylation status of Wnt antagonist SFRP5 can predict the response to the EGFR-tyrosine kinase inhibitor therapy in non-small cell lung cancer

Cited by 40 publications

References 37 publications

Wif1 Hypermethylation as Unfavorable Prognosis of Non-Small Cell Lung Cancers with EGFR Mutation

Wif1 Hypermethylation as Unfavorable Prognosis of Non-Small Cell Lung Cancers with EGFR Mutation

Long-term exposure to gefitinib induces acquired resistance through DNA methylation changes in the EGFR-mutant PC9 lung cancer cell line

Genome-wide DNA Methylation Analysis Reveals GABBR2 as a Novel Epigenetic Target for EGFR 19 Deletion Lung Adenocarcinoma with Induction Erlotinib Treatment

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