Cargando…
EGFR activity addiction facilitates anti-ERBB based combination treatment of squamous bladder cancer
Recent findings suggested a benefit of anti-EGFR therapy for basal-like muscle-invasive bladder cancer (MIBC). However, the impact on bladder cancer with substantial squamous differentiation (Sq-BLCA) and especially pure squamous cell carcinoma (SCC) remains unknown. Therefore, we comprehensively ch...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605436/ https://www.ncbi.nlm.nih.gov/pubmed/32978523 http://dx.doi.org/10.1038/s41388-020-01465-y |
_version_ | 1783604302614364160 |
---|---|
author | Rose, Michael Maurer, Angela Wirtz, Julia Bleilevens, Andreas Waldmann, Tanja Wenz, Maximilian Eyll, Marie Geelvink, Mirja Gereitzig, Melanie Rüchel, Nadine Denecke, Bernd Eltze, Elke Herrmann, Edwin Toma, Marieta Horst, David Grimm, Tobias Denzinger, Stefan Ecke, Thorsten Vögeli, Thomas Alexander Knuechel, Ruth Maurer, Jochen Gaisa, Nadine T. |
author_facet | Rose, Michael Maurer, Angela Wirtz, Julia Bleilevens, Andreas Waldmann, Tanja Wenz, Maximilian Eyll, Marie Geelvink, Mirja Gereitzig, Melanie Rüchel, Nadine Denecke, Bernd Eltze, Elke Herrmann, Edwin Toma, Marieta Horst, David Grimm, Tobias Denzinger, Stefan Ecke, Thorsten Vögeli, Thomas Alexander Knuechel, Ruth Maurer, Jochen Gaisa, Nadine T. |
author_sort | Rose, Michael |
collection | PubMed |
description | Recent findings suggested a benefit of anti-EGFR therapy for basal-like muscle-invasive bladder cancer (MIBC). However, the impact on bladder cancer with substantial squamous differentiation (Sq-BLCA) and especially pure squamous cell carcinoma (SCC) remains unknown. Therefore, we comprehensively characterized pure and mixed Sq-BLCA (n = 125) on genetic and protein expression level, and performed functional pathway and drug-response analyses with cell line models and isolated primary SCC (p-SCC) cells of the human urinary bladder. We identified abundant EGFR expression in 95% of Sq-BLCA without evidence for activating EGFR mutations. Both SCaBER and p-SCC cells were sensitive to EGFR tyrosine kinase inhibitors (TKIs: erlotinib and gefitinib). Combined treatment with anti-EGFR TKIs and varying chemotherapeutics led to a concentration-dependent synergism in SCC cells according to the Chou-Talalay method. In addition, the siRNA knockdown of EGFR impaired SCaBER viability suggesting a putative “Achilles heel” of Sq-BLCA. The observed effects seem Sq-BLCA-specific since non-basal urothelial cancer cells were characterized by poor TKI sensitivity associated with a short-term feedback response potentially attenuating anti-tumor activity. Hence, our findings give further insights into a crucial, Sq-BLCA-specific role of the ERBB signaling pathway proposing improved effectiveness of anti-EGFR based regimens in combination with chemotherapeutics in squamous bladder cancers with wild-type EGFR-overexpression. |
format | Online Article Text |
id | pubmed-7605436 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-76054362020-11-12 EGFR activity addiction facilitates anti-ERBB based combination treatment of squamous bladder cancer Rose, Michael Maurer, Angela Wirtz, Julia Bleilevens, Andreas Waldmann, Tanja Wenz, Maximilian Eyll, Marie Geelvink, Mirja Gereitzig, Melanie Rüchel, Nadine Denecke, Bernd Eltze, Elke Herrmann, Edwin Toma, Marieta Horst, David Grimm, Tobias Denzinger, Stefan Ecke, Thorsten Vögeli, Thomas Alexander Knuechel, Ruth Maurer, Jochen Gaisa, Nadine T. Oncogene Article Recent findings suggested a benefit of anti-EGFR therapy for basal-like muscle-invasive bladder cancer (MIBC). However, the impact on bladder cancer with substantial squamous differentiation (Sq-BLCA) and especially pure squamous cell carcinoma (SCC) remains unknown. Therefore, we comprehensively characterized pure and mixed Sq-BLCA (n = 125) on genetic and protein expression level, and performed functional pathway and drug-response analyses with cell line models and isolated primary SCC (p-SCC) cells of the human urinary bladder. We identified abundant EGFR expression in 95% of Sq-BLCA without evidence for activating EGFR mutations. Both SCaBER and p-SCC cells were sensitive to EGFR tyrosine kinase inhibitors (TKIs: erlotinib and gefitinib). Combined treatment with anti-EGFR TKIs and varying chemotherapeutics led to a concentration-dependent synergism in SCC cells according to the Chou-Talalay method. In addition, the siRNA knockdown of EGFR impaired SCaBER viability suggesting a putative “Achilles heel” of Sq-BLCA. The observed effects seem Sq-BLCA-specific since non-basal urothelial cancer cells were characterized by poor TKI sensitivity associated with a short-term feedback response potentially attenuating anti-tumor activity. Hence, our findings give further insights into a crucial, Sq-BLCA-specific role of the ERBB signaling pathway proposing improved effectiveness of anti-EGFR based regimens in combination with chemotherapeutics in squamous bladder cancers with wild-type EGFR-overexpression. Nature Publishing Group UK 2020-09-25 2020 /pmc/articles/PMC7605436/ /pubmed/32978523 http://dx.doi.org/10.1038/s41388-020-01465-y Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Rose, Michael Maurer, Angela Wirtz, Julia Bleilevens, Andreas Waldmann, Tanja Wenz, Maximilian Eyll, Marie Geelvink, Mirja Gereitzig, Melanie Rüchel, Nadine Denecke, Bernd Eltze, Elke Herrmann, Edwin Toma, Marieta Horst, David Grimm, Tobias Denzinger, Stefan Ecke, Thorsten Vögeli, Thomas Alexander Knuechel, Ruth Maurer, Jochen Gaisa, Nadine T. EGFR activity addiction facilitates anti-ERBB based combination treatment of squamous bladder cancer |
title | EGFR activity addiction facilitates anti-ERBB based combination treatment of squamous bladder cancer |
title_full | EGFR activity addiction facilitates anti-ERBB based combination treatment of squamous bladder cancer |
title_fullStr | EGFR activity addiction facilitates anti-ERBB based combination treatment of squamous bladder cancer |
title_full_unstemmed | EGFR activity addiction facilitates anti-ERBB based combination treatment of squamous bladder cancer |
title_short | EGFR activity addiction facilitates anti-ERBB based combination treatment of squamous bladder cancer |
title_sort | egfr activity addiction facilitates anti-erbb based combination treatment of squamous bladder cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605436/ https://www.ncbi.nlm.nih.gov/pubmed/32978523 http://dx.doi.org/10.1038/s41388-020-01465-y |
work_keys_str_mv | AT rosemichael egfractivityaddictionfacilitatesantierbbbasedcombinationtreatmentofsquamousbladdercancer AT maurerangela egfractivityaddictionfacilitatesantierbbbasedcombinationtreatmentofsquamousbladdercancer AT wirtzjulia egfractivityaddictionfacilitatesantierbbbasedcombinationtreatmentofsquamousbladdercancer AT bleilevensandreas egfractivityaddictionfacilitatesantierbbbasedcombinationtreatmentofsquamousbladdercancer AT waldmanntanja egfractivityaddictionfacilitatesantierbbbasedcombinationtreatmentofsquamousbladdercancer AT wenzmaximilian egfractivityaddictionfacilitatesantierbbbasedcombinationtreatmentofsquamousbladdercancer AT eyllmarie egfractivityaddictionfacilitatesantierbbbasedcombinationtreatmentofsquamousbladdercancer AT geelvinkmirja egfractivityaddictionfacilitatesantierbbbasedcombinationtreatmentofsquamousbladdercancer AT gereitzigmelanie egfractivityaddictionfacilitatesantierbbbasedcombinationtreatmentofsquamousbladdercancer AT ruchelnadine egfractivityaddictionfacilitatesantierbbbasedcombinationtreatmentofsquamousbladdercancer AT deneckebernd egfractivityaddictionfacilitatesantierbbbasedcombinationtreatmentofsquamousbladdercancer AT eltzeelke egfractivityaddictionfacilitatesantierbbbasedcombinationtreatmentofsquamousbladdercancer AT herrmannedwin egfractivityaddictionfacilitatesantierbbbasedcombinationtreatmentofsquamousbladdercancer AT tomamarieta egfractivityaddictionfacilitatesantierbbbasedcombinationtreatmentofsquamousbladdercancer AT horstdavid egfractivityaddictionfacilitatesantierbbbasedcombinationtreatmentofsquamousbladdercancer AT grimmtobias egfractivityaddictionfacilitatesantierbbbasedcombinationtreatmentofsquamousbladdercancer AT denzingerstefan egfractivityaddictionfacilitatesantierbbbasedcombinationtreatmentofsquamousbladdercancer AT eckethorsten egfractivityaddictionfacilitatesantierbbbasedcombinationtreatmentofsquamousbladdercancer AT vogelithomasalexander egfractivityaddictionfacilitatesantierbbbasedcombinationtreatmentofsquamousbladdercancer AT knuechelruth egfractivityaddictionfacilitatesantierbbbasedcombinationtreatmentofsquamousbladdercancer AT maurerjochen egfractivityaddictionfacilitatesantierbbbasedcombinationtreatmentofsquamousbladdercancer AT gaisanadinet egfractivityaddictionfacilitatesantierbbbasedcombinationtreatmentofsquamousbladdercancer |