EGFR activity addiction facilitates anti-ERBB based combination treatment of squamous bladder cancer
Copyright policy )EGFR activity addiction facilitates anti-ERBB based combination treatment of squamous bladder cancer
AbstractRecent 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.
- RWTH Aachen University (Medical Faculty) Germany
- University Hospital Münster Germany
- University Hospital Bonn Germany
- Charité - University Medicine Berlin Germany
- Universitäts-Augenklinik Bonn Germany
Male, Carcinoma, Transitional Cell, Receptor, ErbB-3, Receptor, ErbB-2, Drug Synergism, Gefitinib, Article, Bladder cancer ; Gene Expression Regulation, Neoplastic [MeSH] ; Urinary Bladder/pathology [MeSH] ; Cell Line, Tumor [MeSH] ; Aged [MeSH] ; Receptor, ErbB-2/metabolism [MeSH] ; Drug Synergism [MeSH] ; Urinary Bladder Neoplasms/drug therapy [MeSH] ; Cohort Studies [MeSH] ; Carcinoma, Transitional Cell/pathology [MeSH] ; ErbB Receptors/metabolism [MeSH] ; Carcinoma, Transitional Cell/genetics [MeSH] ; Male [MeSH] ; Carcinoma, Transitional Cell/drug therapy [MeSH] ; Receptor, ErbB-2/antagonists ; Gefitinib/therapeutic use [MeSH] ; Signal Transduction/drug effects [MeSH] ; Urinary Bladder Neoplasms/genetics [MeSH] ; Receptor, ErbB-4/metabolism [MeSH] ; Carcinoma, Squamous Cell/pathology [MeSH] ; Female [MeSH] ; Drug Resistance, Neoplasm/drug effects [MeSH] ; Protein Kinase Inhibitors/pharmacology [MeSH] ; ErbB Receptors/antagonists ; Humans [MeSH] ; Gene Knockdown Techniques [MeSH] ; ErbB Receptors/genetics [MeSH] ; Erlotinib Hydrochloride/therapeutic use [MeSH] ; Receptor, ErbB-3/metabolism [MeSH] ; Urinary Bladder Neoplasms/pathology [MeSH] ; Protein Kinase Inhibitors/therapeutic use [MeSH] ; Carcinoma, Squamous Cell/drug therapy [MeSH] ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use [MeSH] ; Gefitinib/pharmacology [MeSH] ; Article ; Antineoplastic Combined Chemotherapy Protocols/pharmacology [MeSH] ; Receptor, ErbB-4/antagonists ; Growth factor signalling ; Carcinoma, Squamous Cell/genetics [MeSH] ; Receptor, ErbB-3/antagonists ; RNA, Small Interfering/metabolism [MeSH] ; Erlotinib Hydrochloride/pharmacology [MeSH], Cohort Studies, ErbB Receptors, Gene Expression Regulation, Neoplastic, Erlotinib Hydrochloride, Drug Resistance, Neoplasm, Cell Line, Tumor, Gene Knockdown Techniques, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Squamous Cell, Humans, Female, RNA, Small Interfering, Protein Kinase Inhibitors, Aged
Male, Carcinoma, Transitional Cell, Receptor, ErbB-3, Receptor, ErbB-2, Drug Synergism, Gefitinib, Article, Bladder cancer ; Gene Expression Regulation, Neoplastic [MeSH] ; Urinary Bladder/pathology [MeSH] ; Cell Line, Tumor [MeSH] ; Aged [MeSH] ; Receptor, ErbB-2/metabolism [MeSH] ; Drug Synergism [MeSH] ; Urinary Bladder Neoplasms/drug therapy [MeSH] ; Cohort Studies [MeSH] ; Carcinoma, Transitional Cell/pathology [MeSH] ; ErbB Receptors/metabolism [MeSH] ; Carcinoma, Transitional Cell/genetics [MeSH] ; Male [MeSH] ; Carcinoma, Transitional Cell/drug therapy [MeSH] ; Receptor, ErbB-2/antagonists ; Gefitinib/therapeutic use [MeSH] ; Signal Transduction/drug effects [MeSH] ; Urinary Bladder Neoplasms/genetics [MeSH] ; Receptor, ErbB-4/metabolism [MeSH] ; Carcinoma, Squamous Cell/pathology [MeSH] ; Female [MeSH] ; Drug Resistance, Neoplasm/drug effects [MeSH] ; Protein Kinase Inhibitors/pharmacology [MeSH] ; ErbB Receptors/antagonists ; Humans [MeSH] ; Gene Knockdown Techniques [MeSH] ; ErbB Receptors/genetics [MeSH] ; Erlotinib Hydrochloride/therapeutic use [MeSH] ; Receptor, ErbB-3/metabolism [MeSH] ; Urinary Bladder Neoplasms/pathology [MeSH] ; Protein Kinase Inhibitors/therapeutic use [MeSH] ; Carcinoma, Squamous Cell/drug therapy [MeSH] ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use [MeSH] ; Gefitinib/pharmacology [MeSH] ; Article ; Antineoplastic Combined Chemotherapy Protocols/pharmacology [MeSH] ; Receptor, ErbB-4/antagonists ; Growth factor signalling ; Carcinoma, Squamous Cell/genetics [MeSH] ; Receptor, ErbB-3/antagonists ; RNA, Small Interfering/metabolism [MeSH] ; Erlotinib Hydrochloride/pharmacology [MeSH], Cohort Studies, ErbB Receptors, Gene Expression Regulation, Neoplastic, Erlotinib Hydrochloride, Drug Resistance, Neoplasm, Cell Line, Tumor, Gene Knockdown Techniques, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Squamous Cell, Humans, Female, RNA, Small Interfering, Protein Kinase Inhibitors, Aged
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