A two-step toward personalized therapies for prostate cancer

Abstract

Identifying the dominant genetic alterations that drive tumorigenesis is essential for developing targeted cancer therapies. Recent work has demonstrated that prostate tumors can be stratified by dominant genetic alterations, such as chromosomal rearrangements involving ETS (Erythroblastosis virus E26 transformation-specific) family transcription factors or overexpression of SPINK1, a gene that encodes a secreted serine protease inhibitor. In this issue of Science Translational Medicine, Ateeq et al. provide evidence to support a rationale for targeting the SPINK1 protein in the SPINK1+/ETS⁻ subset of prostate tumors and also describe a potential interaction of SPINK1 with epidermal growth factor receptor that could be an additional target for therapeutic intervention.

Fig. 1. Targeted therapies

(A) SPINK1 secreted from prostate cancer cells can stimulate EGFR dimerization, phosphorylation and downstream signaling through phosphoinositide-3-kinase (PI3K)/AKT, mitogen activated protein kinase (MAPK), or janus kinase (JAK) pathways in an autocrine loop. (B) In addition to small-molecule agents that block AR, PI3K/AKT, MAPK, or JAK signaling pathways, monoclonal antibodies against EGFR or SPINK1 could inhibit signal transduction by blocking the physical interaction between EGFR and the SPINK1 ligand. Antibody inhibition of EGFR-SPINK1 binding would cause receptor endocytosis and EGFR down-regulation, subsequently breaking the autocrine loop. Antibodies targeting EGFR would specifically block receptor dimerization, autophosphorylation, and downstream signaling. The effects of SPINK1 cannot be completely reversed by inhibition of EGFR, suggesting that SPINK1 may act as a ligand for other receptors or promote aggressive properties through other mechanisms.