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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

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  • Medientyp: E-Artikel
  • Titel: EGFR activity addiction facilitates anti-ERBB based combination treatment of squamous bladder cancer
  • Beteiligte: 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.
  • Erschienen: Springer Science and Business Media LLC, 2020
  • Erschienen in: Oncogene
  • Sprache: Englisch
  • DOI: 10.1038/s41388-020-01465-y
  • ISSN: 0950-9232; 1476-5594
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title><jats:p>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 (<jats:italic>n</jats:italic> = 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 <jats:italic>EGFR</jats:italic> 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.</jats:p>