Mechanistic Support for Combined MET and AR Blockade in Castration-Resistant Prostate Cancer

• DOI: 10.1016/j.neo.2015.11.009
• Publication Date: 2016-01-22T00:06:00Z
• Authors: Yuanyuan Qiao; Felix Y. Feng; Yugang Wang; Xuhong Cao; Sumin Han; Kari Wilder-Romans; Nora M. Navone; Christopher Logot...; Russell S. Taichman; Evan T. Keller; Ganesh S. Palapattu; Ajjai S. Alva; David C. Smith; Scott A. Tomlins; Arul M. Chinnaiyan; Todd M. Morgan
• Keywords: Cabozantinib; Enzalutamide

A recent phase III trial of the MET kinase inhibitor cabozantinib in men with castration-resistant prostate cancer (CRPC) failed to meet its primary survival end point; however, most CRPC have intact androgen receptor (AR) signaling. As previous work supports negative regulation by AR signaling, we hypothesized that signaling may limited efficacy some these patients. To assess role on inhibition, first performed an silico analysis human tissue samples stratified status (+ or −), which identified expression as markedly increased AR− samples. In vitro, inhibition AR+ models and resulted susceptibility ligand (HGF) activation. Likewise, was only effective blocking phenotypes cells overexpression. Using multiple vitro vivo models, showed combined enzalutamide (AR antagonist) treatment more efficacious than either alone. These data provide a compelling rationale combine explain results study CRPC. Similarly, disease, whether due loss suggests potential utility for select patients therapy resistance cancer.