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

ABSTRACT: Recent findings suggested a benefit of anti-EGFR therapy for basal-like muscle invasive bladder cancer (MIBC). However, impact on bladder cancer with substantial squamous differentiated (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, 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 by upregulating EGFR and ERBB3 expression. Hence, our findings give novel insights into a crucial, Sq-BLCA-specific role of the ERBB signaling pathway proposing improved effectiveness of combined anti-EGFR and chemotherapeutic regimens in squamous bladder cancers with wild-type EGFR-overexpression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE146975 | GEO | 2023/03/12

REPOSITORIES: GEO

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