BMX-Mediated Regulation of Multiple Tyrosine Kinases Contributes to Castration Resistance in Prostate Cancer
Abstract
Prostate cancer responds to therapies that suppress androgen receptor (AR) activity (androgen deprivation therapy, ADT) but invariably progresses to castration-resistant prostate cancer (CRPC). The Tec family nonreceptor tyrosine kinase BMX is activated downstream of PI3K and has been implicated in regulation of multiple pathways and in the development of cancers including prostate cancer. However, its precise mechanisms of action, and particularly its endogenous substrates, remain to be established. Here, we demonstrate that BMX expression in prostate cancer is suppressed directly by AR via binding to the BMX gene and that BMX expression is subsequently rapidly increased in response to ADT. BMX contributed to CRPC development in cell line and xenograft models by positively regulating the activities of multiple receptor tyrosine kinases through phosphorylation of a phosphotyrosine-tyrosine (pYY) motif in their activation loop, generating pYpY that is required for full kinase activity. To assess BMX activity in vivo, we generated a BMX substrate–specific antibody (anti-pYpY) and found that its reactivity correlated with BMX expression in clinical samples, supporting pYY as an in vivo substrate. Inhibition of BMX with ibrutinib (developed as an inhibitor of the related Tec kinase BTK) or another BMX inhibitor BMX-IN-1 markedly enhanced the response to castration in a prostate cancer xenograft model. These data indicate that increased BMX in response to ADT contributes to enhanced tyrosine kinase signaling and the subsequent emergence of CRPC, and that combination therapies targeting AR and BMX may be effective in a subset of patients.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Sep 14, 2018
- Source ID
- 10.1158/0008-5472.can-17-3615
Entities
People
- Adam G Sowalsky
- Changmeng Cai
- Fen Ma
- Huihui Ye
- Nathanael Gray
- Nicholas I. Simon
- Sen Chen
- Steven P Balk
- Xin Yuan
Organizations
- Beth Israel Deaconess Medical Center
- Dana–Farber Cancer Institute
- Harvard Medical School
- National Cancer Institute
- National Institutes of Health
- United States Department of Defense
- University of Massachusetts Boston