Abstract
Growth factor receptor tyrosine kinase (RTK) pathway activation is a key mechanism for mediating cancer growth, survival, and treatment resistance. Cognate ligands play crucial roles in autocrine or paracrine stimulation of these RTK pathways. Here, we show SEMA3C drives activation of multiple RTKs including EGFR, ErbB2, and MET in a cognate ligand‐independent manner via Plexin B1. SEMA3C expression levels increase in castration‐resistant prostate cancer (CRPC), where it functions to promote cancer cell growth and resistance to androgen receptor pathway inhibition. SEMA3C inhibition delays CRPC and enzalutamide‐resistant progression. Plexin B1 sema domain‐containing:Fc fusion proteins suppress RTK signaling and cell growth and inhibit CRPC progression of LNCaP xenografts post‐castration in vivo. SEMA3C inhibition represents a novel therapeutic strategy for treatment of advanced prostate cancer.
Highlights
Androgen deprivation therapy (ADT) is first-line systemic therapy for men with metastatic prostate cancer (PCa)
To define SEMA3C-Fc fusion protein (SEMA3C) expression levels in benign and cancerous prostate specimens and bone metastases, we assessed the levels of SEMA3C by tissue microarray (TMA) immunohistochemical (IHC) staining of a panel of 280 human PCa specimens representing benign prostatic hyperplasia (BPH, n = 12), untreated hormone naive (n = 114), neo-adjuvant hormone therapy (NHT)-treated (n = 87), NHT- and docetaxel-treated (n = 53) radical prostatectomy PCa specimens, as well as castration-resistant prostate cancer (CRPC) bone metastases (n = 30) collected immediately after death via University of Washington Rapid Autopsy program (Rocchi et al, 2005)
We validated the specificity of SEMA3C (N20) antibodies to detect SEMA3C in DU145 cells transfected with scramble or SEMA3C siRNA using confocal immunofluorescent microscopy
Summary
Androgen deprivation therapy (ADT) is first-line systemic therapy for men with metastatic prostate cancer (PCa). Development of CRPC is a complex process that has been attributed to a variety of mechanisms including reactivation of the androgen receptor (AR) axis and activation of growth factor signaling pathways (Yap et al, 2011). Our gene expression profiling data identified SEMA3C, a member of the secreted class 3 semaphorins, as a highly expressed gene in CRPC and AR pathway inhibitor-recurrent tumors. In search of novel targets associated with expression of PTEN, a gene that is frequently mutated in advanced PCa, DNA microarray profiling identified SEMA3C among the top three most differentially expressed genes between PTEN+ vs PTENÀ/À cancer cells (Peacock et al, 2009). While semaphorins have been best characterized in the nervous system, they have been implicated in a variety of dynamic physiological processes including angiogenesis, tissue morphogenesis, immunity, and cancer (Cagnoni & Tamagnone, 2014)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
