EGFR activity addiction facilitates anti-ERBB based combination treatment of squamous bladder cancer

• Published in: Oncogene 2020-10, Vol.39 (44), p.6856-6870
• Main Authors: 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.
• Format: Article
• Language: English
• Subjects: 13/106; 13/51; 38/61; 38/77; 42/109; 42/89; 631/67/589/1336; 631/80/86/2368; 82/80; 96/63; 96/95; Addictions; Aged; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Antitumor agents; Apoptosis; Biological response modifiers; Bladder cancer; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - pathology; Carcinoma, Transitional Cell - drug therapy; Carcinoma, Transitional Cell - genetics; Carcinoma, Transitional Cell - pathology; Care and treatment; Cell Biology; Cell culture; Cell Line, Tumor; Cohort Studies; Combined modality therapy; Drug Resistance, Neoplasm - drug effects; Drug Synergism; Epidermal growth factor receptors; ErbB protein; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - genetics; ErbB Receptors - metabolism; Erlotinib Hydrochloride - pharmacology; Erlotinib Hydrochloride - therapeutic use; Female; Gefitinib; Gefitinib - pharmacology; Gefitinib - therapeutic use; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Genetic aspects; Human Genetics; Humans; Internal Medicine; Invasiveness; Kinases; Male; Medicine; Medicine & Public Health; Methods; Oncology; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein-tyrosine kinase; Receptor, ErbB-2 - antagonists & inhibitors; Receptor, ErbB-2 - metabolism; Receptor, ErbB-3 - antagonists & inhibitors; Receptor, ErbB-3 - metabolism; Receptor, ErbB-4 - antagonists & inhibitors; Receptor, ErbB-4 - metabolism; RNA, Small Interfering - metabolism; Signal transduction; Signal Transduction - drug effects; siRNA; Squamous cell carcinoma; Urinary bladder; Urinary Bladder - pathology; Urinary Bladder Neoplasms - drug therapy; Urinary Bladder Neoplasms - genetics; Urinary Bladder Neoplasms - pathology; Urothelial cancer
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-020-01465-y

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.