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

Autor: Rose M; Institute of Pathology, RWTH Aachen University, Aachen, Germany., Maurer A; Institute of Pathology, RWTH Aachen University, Aachen, Germany., Wirtz J; Institute of Pathology, RWTH Aachen University, Aachen, Germany., Bleilevens A; Department of Gynecology, University Clinic RWTH, Aachen, Germany., Waldmann T; Department of Gynecology, University Clinic RWTH, Aachen, Germany., Wenz M; Institute of Pathology, RWTH Aachen University, Aachen, Germany., Eyll M; Institute of Pathology, RWTH Aachen University, Aachen, Germany., Geelvink M; Institute of Pathology, RWTH Aachen University, Aachen, Germany., Gereitzig M; Institute of Pathology, RWTH Aachen University, Aachen, Germany., Rüchel N; Institute of Pathology, RWTH Aachen University, Aachen, Germany., Denecke B; IZKF Aachen, Medical Faculty of the RWTH Aachen University, Aachen, Germany., Eltze E; Institute of Pathology, Saarbrücken-Rastpfuhl, Saarbrücken, Germany., Herrmann E; Department of Urology, University Hospital Münster, Münster, Germany., Toma M; Institute of Pathology, University Hospital Gustav Carus TU Dresden, Dresden, Germany.; Institute of Pathology, University Hospital Bonn, Bonn, Germany., Horst D; Institute of Pathology, Charité - Universitätsmedizin Berlin, Berlin, Germany., Grimm T; Department of Urology, LMU Munich, Munich, Germany., Denzinger S; Department of Urology, University of Regensburg, Regensburg, Germany., Ecke T; Department of Urology, Helios Hospital Bad Saarow, Bad Saarow, Germany., Vögeli TA; Department of Urology, RWTH Aachen University, Aachen, Germany., Knuechel R; Institute of Pathology, RWTH Aachen University, Aachen, Germany., Maurer J; Department of Gynecology, University Clinic RWTH, Aachen, Germany., Gaisa NT; Institute of Pathology, RWTH Aachen University, Aachen, Germany. ngaisa@ukaachen.de.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2020 Oct; Vol. 39 (44), pp. 6856-6870. Date of Electronic Publication: 2020 Sep 25.
DOI: 10.1038/s41388-020-01465-y
Abstrakt: 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.
Databáze: MEDLINE
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