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

Terai, Hideki; Soejima, Kenzo; Yasuda, Hiroyuki; Sato, Takashi; Naoki, Katsuhiko; Ikemura, Shinnosuke; Arai, Daisuke; Ohgino, Keiko; Ishioka, Kota; Hamamoto, Junko; Kanai, Yae; Betsuyaku, Tomoko

doi:10.3892/ijo.2014.2733

Cited by 11 publications

(7 citation statements)

References 26 publications

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“…We compared the differentially expressed mRNAs with other studies, and the high consistency strongly supported our predictions. For example, in the mRNA expression analysis using Agilent SurePrint G3 Human Gene Expression 8x60K array of a gefitinib-resistant lung cancer cell line (19), IGFBP3 was found to be expressed differentially, which is in accordance with our results. Additionally, the constitutive activation of EGFR tyrosine kinase receptor caused by mutation and/or amplification is closely correlated with the development, progression and poor prognosis of NSCLC, through the activation of various downstream signaling pathways.…”

Section: Discussionsupporting

confidence: 90%

Genome-wide profiling of long non-coding RNA expression patterns in the EGFR-TKI resistance of lung adenocarcinoma by microarray

et al. 2016

Oncology Reports

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Abstract. Mutations in the epidermal growth factor receptor (EGFR) make lung adenocarcinoma cells sensitive to EGFR tyrosine kinase inhibitors (TKIs). Long-term cancer therapy may cause the occurrence of acquired resistance to EGFR TKIs. Long non-coding RNAs (lncRNAs) play important roles in tumor formation, tumor metastasis and the development of EGFR-TKI resistance in lung cancer. To gain insight into the molecular mechanisms of EGFR-TKI resistance, we generated an EGFR-TKI-resistant HCC827-8-1 cell line and analyzed expression patterns by lncRNA microarray and compared it with its parental HCC827 cell line. A total of 1,476 lncRNA transcripts and 1,026 mRNA transcripts were dysregulated in the HCC827-8-1 cells. The expression levels of 7 chosen lncRNAs were validated by real-time quantitative PCR. As indicated by functional analysis, several groups of lncRNAs may be involved in the bio-pathways associated with EGFR-TKI resistance through their cis-and/or trans-regulation of protein-coding genes. Thus, lncRNAs may be used as novel candidate biomarkers and potential targets in EGFR-TKI therapy in the future.

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Section: Discussionsupporting

confidence: 90%

Genome-wide profiling of long non-coding RNA expression patterns in the EGFR-TKI resistance of lung adenocarcinoma by microarray

et al. 2016

Oncology Reports

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“…Two previous studies were identified that had used mRNA microarray analysis to examine changes of gene expression in lung cancer cells with acquired resistance to either gefitinib or erlotinib (12,31). However, these studies only examined one cell line resistant to either gefitinib or erlotinib.…”

Section: Discussionmentioning

confidence: 99%

Altered expression of cellular proliferation, apoptosis and the cell cycle-related genes in lung cancer cells with acquired resistance to EGFR tyrosine kinase inhibitors

Lee¹,

Jeong²,

Min³

et al. 2017

Oncology Letters

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Non-small cell lung cancers harboring somatic gain-of-function mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase domain respond well to treatment with EGFR tyrosine kinase inhibitors (TKIs) including gefitinib and erlotinib. However, all patients who experience a marked improvement with these drugs eventually develop disease progression due to the acquisition of drug resistance. Approximately half of the cases with acquired resistance to EGFR TKIs can be accounted for by a second-site mutation in exon 20 of the EGFR kinase domain (T790M). However, the changes of gene expression involved in EGFR TKI resistance due to the T790M mutation remain poorly defined. The present study established lung cancer cell lines that were resistant to gefitinib or erlotinib, and these cell lines were verified to contain the EGFR T790M mutation. The differential expression of genes associated with acquired resistance was verified in the present study by mRNA microarray analysis. Among the genes whose expression was significantly altered, genes whose expression was altered in gefitinib- and erlotinib-resistant cells were focused on. Notably, a total of 1,617 genes were identified as being differentially expressed in gefitinib- and erlotinib-resistant cells. Indeed, Gene ontology analysis revealed altered expression of genes involved in the regulation of cellular proliferation, apoptosis, and the cell cycle in EGFR TKI-resistant cells. The present results demonstrate distinctive gene expression patterns of EGFR TKI-resistant lung cancer cells with the EGFR T790M mutation. The present study can provide key insights into gene expression profiles involved in conferring resistance to EGFR TKI therapy in lung cancer cells.

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“…It appears that high level of IGFBP3 is a protective factor and is associated with good prognosis in patients with advanced NSCLC (13)(14)(15). No cases of IGFBP3 gene deletion in humans have been reported, but hypermethylation of the IGFBP3 promoter is involved in loss of IGFBP3 expression in NSCLC, and may be related to the development of acquired treatment resistance (16)(17)(18)(19). Although a prior report has shown that heterozygously deleted Igfbp3 transgenic mice with mutant IGF1 expression have higher lung tumorigenesis, there was no increased tumorigenesis in homozygously deleted Igfbp3 mice compared with wild-type Igfbp3 control, which was unexplained (20).…”

Section: Introductionmentioning

confidence: 99%

IGFBP3 Modulates Lung Tumorigenesis and Cell Growth through IGF1 Signaling

Wang

Sun

Palmer

et al. 2017

Molecular Cancer Research

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Insulin-like growth factor binding protein 3 (IGFBP3) modulates cell growth through IGF-dependent and -independent mechanisms. Reports suggest that the serum levels of IGFBP3 are associated with various cancers and that IGFBP3 expression is significantly decreased in cisplatin (CDDP)-resistant lung cancer cells. Based on these findings, we investigated whether deficiency accelerates mouse lung tumorigenesis and if expression of IGFBP3 enhances CDDP response by focusing on the IGF1 signaling cascade. To this end, an-null mouse model was generated in combination with to compare the tumor burden. Then, IGF-dependent signaling was assessed after expressing wild-type or a mutant IGFBP3 without IGF binding capacity in non-small cell lung cancer (NSCLC) cells. Finally, the treatment response to CDDP chemotherapy was evaluated under conditions of IGFBP3 overexpression.-null mice had increased lung tumor burden (>2-fold) and only half of human lung cancer cells survived after expression of IGFBP3, which corresponded to increased cleaved caspase-3 (10-fold), inactivation of IGF1 and MAPK signaling. In addition, overexpression of IGFBP3 increased susceptibility to CDDP treatment in lung cancer cells. These results, for the first time, demonstrate that IGFBP3 mediates lung cancer progression in a mouse model. Furthermore, overexpression of IGFBP3 induced apoptosis and enhanced cisplatin response and confirmed that the suppression is in part by blocking IGF1 signaling. These findings reveal that IGFBP3 is effective in lung cancer cells with high IGF1 signaling activity and imply that relevant biomarkers are essential in selecting lung cancer patients for IGF1-targeted therapy. .

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

Cited by 11 publications

References 26 publications

Genome-wide profiling of long non-coding RNA expression patterns in the EGFR-TKI resistance of lung adenocarcinoma by microarray

Genome-wide profiling of long non-coding RNA expression patterns in the EGFR-TKI resistance of lung adenocarcinoma by microarray

Altered expression of cellular proliferation, apoptosis and the cell cycle-related genes in lung cancer cells with acquired resistance to EGFR tyrosine kinase inhibitors

IGFBP3 Modulates Lung Tumorigenesis and Cell Growth through IGF1 Signaling

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