{"title":"Targeting EGFR Activation to Overcome Gemcitabine Resistance in Cholangiocarcinoma.","authors":"Sonexai Kidoikhammouan, Worachart Lert-Itthiporn, Raksawan Deenonpoe, Charupong Saengboonmee, Sumalee Obchoei, Sopit Wongkham, Wunchana Seubwai","doi":"10.21873/anticanres.17366","DOIUrl":null,"url":null,"abstract":"<p><strong>Background/aim: </strong>Chemotherapy resistance is an important problem in the treatment of patients with cholangiocarcinoma (CCA) who are not eligible for surgery. This study aimed to overcome gemcitabine (Gem) resistance in CCA by investigating and targeting Gem resistance-associated molecules.</p><p><strong>Materials and methods: </strong>Three stable Gem-resistant CCA cell lines (CCA-GemR) were established by gradually exposing CCA cell lines to Gem. The cells were characterized in terms of growth, cross-resistance to chemotherapeutic drugs, cell cycle distribution, and colony formation. The molecular mechanisms related to Gem resistance were assessed using a phosphorylation array assay and protein expression was confirmed using western blotting analysis. The targeted molecules were subsequently analyzed using PanDrugs to identify potential targeted therapies. The drug was used to enhance Gem sensitivity.</p><p><strong>Results: </strong>The results demonstrated that CCA-GemR cells grow more slowly compared to their parental cell lines. Cell cycle analysis revealed an increase in KKU-213A-GemR and KKU-213B-GemR cell accumulation in the G1 phase. Moreover, cross-resistance to 5-FU and cisplatin was observed in all CCA-GemR cells. The Proteome Profiler Human Phospho-Kinase Array showed increased phosphorylation of EGFR in CCA-GemR cells. Erlotinib, a specific inhibitor of EGFR, significantly enhanced the anti-tumor activity of Gem with a synergistic effect (Combination index <1). Western blot analysis confirmed that phosphorylation of EGFR increased in cells treated with Gem, whereas the expression was significantly decreased in cells treated with either erlotinib alone or in combination with Gem.</p><p><strong>Conclusion: </strong>EGFR is a potential target molecule for reducing Gem resistance and enhancing its anti-tumor effects in patients with CCA.</p>","PeriodicalId":8072,"journal":{"name":"Anticancer research","volume":"44 12","pages":"5393-5404"},"PeriodicalIF":1.6000,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Anticancer research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.21873/anticanres.17366","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background/aim: Chemotherapy resistance is an important problem in the treatment of patients with cholangiocarcinoma (CCA) who are not eligible for surgery. This study aimed to overcome gemcitabine (Gem) resistance in CCA by investigating and targeting Gem resistance-associated molecules.
Materials and methods: Three stable Gem-resistant CCA cell lines (CCA-GemR) were established by gradually exposing CCA cell lines to Gem. The cells were characterized in terms of growth, cross-resistance to chemotherapeutic drugs, cell cycle distribution, and colony formation. The molecular mechanisms related to Gem resistance were assessed using a phosphorylation array assay and protein expression was confirmed using western blotting analysis. The targeted molecules were subsequently analyzed using PanDrugs to identify potential targeted therapies. The drug was used to enhance Gem sensitivity.
Results: The results demonstrated that CCA-GemR cells grow more slowly compared to their parental cell lines. Cell cycle analysis revealed an increase in KKU-213A-GemR and KKU-213B-GemR cell accumulation in the G1 phase. Moreover, cross-resistance to 5-FU and cisplatin was observed in all CCA-GemR cells. The Proteome Profiler Human Phospho-Kinase Array showed increased phosphorylation of EGFR in CCA-GemR cells. Erlotinib, a specific inhibitor of EGFR, significantly enhanced the anti-tumor activity of Gem with a synergistic effect (Combination index <1). Western blot analysis confirmed that phosphorylation of EGFR increased in cells treated with Gem, whereas the expression was significantly decreased in cells treated with either erlotinib alone or in combination with Gem.
Conclusion: EGFR is a potential target molecule for reducing Gem resistance and enhancing its anti-tumor effects in patients with CCA.
期刊介绍：
ANTICANCER RESEARCH is an independent international peer-reviewed journal devoted to the rapid publication of high quality original articles and reviews on all aspects of experimental and clinical oncology. Prompt evaluation of all submitted articles in confidence and rapid publication within 1-2 months of acceptance are guaranteed.
ANTICANCER RESEARCH was established in 1981 and is published monthly (bimonthly until the end of 2008). Each annual volume contains twelve issues and index. Each issue may be divided into three parts (A: Reviews, B: Experimental studies, and C: Clinical and Epidemiological studies).
Special issues, presenting the proceedings of meetings or groups of papers on topics of significant progress, will also be included in each volume. There is no limitation to the number of pages per issue.
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