Acquired vulnerability against EGF receptor inhibition in gastric cancer promoted by class I histone deacetylase inhibitor entinostat
Introduction: Histone deacetylase inhibitors (HDACi) have shown promising preclinical activity in gastric cancer cells; unfortunately, however, these could not be confirmed in clinical trials. This highlights the need for the identification of underlying reasons, which may also provide the basis for...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-02-01
|
| Series: | Neoplasia: An International Journal for Oncology Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558624001623 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832557600709804032 |
|---|---|
| author | Tamara Zenz Robert Jenke Denys Oliinyk Sandra Noske René Thieme Tim Kahl Ines Gockel Florian Meier-Rosar Achim Aigner Thomas RH Büch |
| author_facet | Tamara Zenz Robert Jenke Denys Oliinyk Sandra Noske René Thieme Tim Kahl Ines Gockel Florian Meier-Rosar Achim Aigner Thomas RH Büch |
| author_sort | Tamara Zenz |
| collection | DOAJ |
| description | Introduction: Histone deacetylase inhibitors (HDACi) have shown promising preclinical activity in gastric cancer cells; unfortunately, however, these could not be confirmed in clinical trials. This highlights the need for the identification of underlying reasons, which may also provide the basis for possible combination therapies. Here, we delineated the effects of HDACi on components of EGFR signalling in gastric cancer cells. Methods: We investigated entinostat effects on EGFR and amphiregulin (AREG) expression in various cell line- and primary patient tumor-based in vitro, ex vivo and in vivo models, on the mRNA and protein level. Based on these results, a combined entinostat plus EGFR inhibitor erlotinib treatment in vitro and in vivo was studied. Results: Proteomics analyses in gastric cancer cells treated with entinostat revealed a marked upregulation of EGFR in the majority of cell lines and an even more robust induction of the EGFR ligand AREG. This was confirmed in a panel of different cell lines in vitro, in tumor tissue-slice cultures ex vivo and in cell line- or patient-derived tumor xenografts in mice. Since previous studies in other tumor entities showed a downregulation of EGFR by HDACi, our findings thus indicate essential differences in the adaptive response of gastric carcinoma cells. Moreover, our results provided the basis for combined entinostat + EGFR inhibitor (erlotinib) treatment, and indeed we demonstrate synergistic effects in combination therapy studies. Conclusion: Our findings establish the profound upregulation of the EGFR/AREG axis by entinostat as starting point for a rational combination therapy in gastric carcinoma. |
| format | Article |
| id | doaj-art-c2a7053afe434aa0a02979f7ac770501 |
| institution | Kabale University |
| issn | 1476-5586 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj-art-c2a7053afe434aa0a02979f7ac7705012025-02-03T04:16:36ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55862025-02-0160101121Acquired vulnerability against EGF receptor inhibition in gastric cancer promoted by class I histone deacetylase inhibitor entinostatTamara Zenz0Robert Jenke1Denys Oliinyk2Sandra Noske3René Thieme4Tim Kahl5Ines Gockel6Florian Meier-Rosar7Achim Aigner8Thomas RH Büch9Leipzig University, Medical Faculty, Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Leipzig, GermanyLeipzig University, Medical Faculty, Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Leipzig, Germany; University Cancer Center Leipzig (UCCL), University Hospital Leipzig, Leipzig, Germany; Comprehensive Cancer Center Central Germany (CCCG), Leipzig and JenaComprehensive Cancer Center Central Germany (CCCG), Leipzig and Jena; Jena University Hospital, Functional Proteomics, Research Center Lobeda, Jena, GermanyLeipzig University, Medical Faculty, Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Leipzig, GermanyComprehensive Cancer Center Central Germany (CCCG), Leipzig and Jena; Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, GermanyLeipzig University, Medical Faculty, Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Leipzig, Germany; Division of Oncology/Hematology, Cantonal Hospital Graubünden, Chur, SwitzerlandComprehensive Cancer Center Central Germany (CCCG), Leipzig and Jena; Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, GermanyComprehensive Cancer Center Central Germany (CCCG), Leipzig and Jena; Jena University Hospital, Functional Proteomics, Research Center Lobeda, Jena, GermanyLeipzig University, Medical Faculty, Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Leipzig, Germany; Comprehensive Cancer Center Central Germany (CCCG), Leipzig and Jena; Corresponding authors at: Dr. Achim Aigner, Leipzig University, Medical Faculty, Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, D-04107 Leipzig, Germany.Leipzig University, Medical Faculty, Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Leipzig, Germany; Comprehensive Cancer Center Central Germany (CCCG), Leipzig and Jena; Corresponding authors at: Dr. Achim Aigner, Leipzig University, Medical Faculty, Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, D-04107 Leipzig, Germany.Introduction: Histone deacetylase inhibitors (HDACi) have shown promising preclinical activity in gastric cancer cells; unfortunately, however, these could not be confirmed in clinical trials. This highlights the need for the identification of underlying reasons, which may also provide the basis for possible combination therapies. Here, we delineated the effects of HDACi on components of EGFR signalling in gastric cancer cells. Methods: We investigated entinostat effects on EGFR and amphiregulin (AREG) expression in various cell line- and primary patient tumor-based in vitro, ex vivo and in vivo models, on the mRNA and protein level. Based on these results, a combined entinostat plus EGFR inhibitor erlotinib treatment in vitro and in vivo was studied. Results: Proteomics analyses in gastric cancer cells treated with entinostat revealed a marked upregulation of EGFR in the majority of cell lines and an even more robust induction of the EGFR ligand AREG. This was confirmed in a panel of different cell lines in vitro, in tumor tissue-slice cultures ex vivo and in cell line- or patient-derived tumor xenografts in mice. Since previous studies in other tumor entities showed a downregulation of EGFR by HDACi, our findings thus indicate essential differences in the adaptive response of gastric carcinoma cells. Moreover, our results provided the basis for combined entinostat + EGFR inhibitor (erlotinib) treatment, and indeed we demonstrate synergistic effects in combination therapy studies. Conclusion: Our findings establish the profound upregulation of the EGFR/AREG axis by entinostat as starting point for a rational combination therapy in gastric carcinoma.http://www.sciencedirect.com/science/article/pii/S1476558624001623Gastric cancerEntinostatEGFRAmphiregulinHistone deacetylasesHDAC inhibition |
| spellingShingle | Tamara Zenz Robert Jenke Denys Oliinyk Sandra Noske René Thieme Tim Kahl Ines Gockel Florian Meier-Rosar Achim Aigner Thomas RH Büch Acquired vulnerability against EGF receptor inhibition in gastric cancer promoted by class I histone deacetylase inhibitor entinostat Neoplasia: An International Journal for Oncology Research Gastric cancer Entinostat EGFR Amphiregulin Histone deacetylases HDAC inhibition |
| title | Acquired vulnerability against EGF receptor inhibition in gastric cancer promoted by class I histone deacetylase inhibitor entinostat |
| title_full | Acquired vulnerability against EGF receptor inhibition in gastric cancer promoted by class I histone deacetylase inhibitor entinostat |
| title_fullStr | Acquired vulnerability against EGF receptor inhibition in gastric cancer promoted by class I histone deacetylase inhibitor entinostat |
| title_full_unstemmed | Acquired vulnerability against EGF receptor inhibition in gastric cancer promoted by class I histone deacetylase inhibitor entinostat |
| title_short | Acquired vulnerability against EGF receptor inhibition in gastric cancer promoted by class I histone deacetylase inhibitor entinostat |
| title_sort | acquired vulnerability against egf receptor inhibition in gastric cancer promoted by class i histone deacetylase inhibitor entinostat |
| topic | Gastric cancer Entinostat EGFR Amphiregulin Histone deacetylases HDAC inhibition |
| url | http://www.sciencedirect.com/science/article/pii/S1476558624001623 |
| work_keys_str_mv | AT tamarazenz acquiredvulnerabilityagainstegfreceptorinhibitioningastriccancerpromotedbyclassihistonedeacetylaseinhibitorentinostat AT robertjenke acquiredvulnerabilityagainstegfreceptorinhibitioningastriccancerpromotedbyclassihistonedeacetylaseinhibitorentinostat AT denysoliinyk acquiredvulnerabilityagainstegfreceptorinhibitioningastriccancerpromotedbyclassihistonedeacetylaseinhibitorentinostat AT sandranoske acquiredvulnerabilityagainstegfreceptorinhibitioningastriccancerpromotedbyclassihistonedeacetylaseinhibitorentinostat AT renethieme acquiredvulnerabilityagainstegfreceptorinhibitioningastriccancerpromotedbyclassihistonedeacetylaseinhibitorentinostat AT timkahl acquiredvulnerabilityagainstegfreceptorinhibitioningastriccancerpromotedbyclassihistonedeacetylaseinhibitorentinostat AT inesgockel acquiredvulnerabilityagainstegfreceptorinhibitioningastriccancerpromotedbyclassihistonedeacetylaseinhibitorentinostat AT florianmeierrosar acquiredvulnerabilityagainstegfreceptorinhibitioningastriccancerpromotedbyclassihistonedeacetylaseinhibitorentinostat AT achimaigner acquiredvulnerabilityagainstegfreceptorinhibitioningastriccancerpromotedbyclassihistonedeacetylaseinhibitorentinostat AT thomasrhbuch acquiredvulnerabilityagainstegfreceptorinhibitioningastriccancerpromotedbyclassihistonedeacetylaseinhibitorentinostat |