SEMA3C drives cancer growth by transactivating multiple receptor tyrosine kinases via Plexin B1

James W. Peacock, Ario Takeuchi, Norihiro Hayashi, Liangliang Liu, Kevin J. Tam, Nader Al Nakouzi, Nastaran Khazamipour, Tabitha Tombe, Takashi Dejima, Kevin C.K. Lee, Masaki Shiota, Daksh Thaper, Wilson C.W. Lee, Daniel H.F. Hui, Hidetoshi Kuruma, Larissa Ivanova, Parvin Yenki, Ivy Z.F. Jiao, Shahram Khosravi, Alice L.F. MuiLadan Fazli, Amina Zoubeidi, Mads Daugaard, Martin E. Gleave, Christopher J. Ong

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)219-238
Number of pages20
JournalEMBO Molecular Medicine
Volume10
Issue number2
DOIs
Publication statusPublished - Feb 1 2018

All Science Journal Classification (ASJC) codes

  • Molecular Medicine

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