Prostate tumor RON receptor signaling mediates macrophage recruitment to drive androgen deprivation therapy resistance through Gas6‐mediated Axl and RON signaling

Background Androgen deprivation therapy (ADT), or chemical castration, is the first‐line therapy for prostate cancer; however, resistance leaves few treatment options. Prostatic tumor‐associated macrophages (TAMs) have been shown to promote prostate cancer growth and are abundant in castration‐resistant prostate cancer (CRPC), suggesting a role in promoting CRPC. We recently showed a tumor cell‐intrinsic mechanism by which RON promotes CRPC. Given previous reports that RON alters prostate cancer cell chemokine production and RON‐overexpressing tumors alter macrophage function, we hypothesized that a macrophage‐dependent mechanism regulated by tumor cell intrinsic RON also promotes CRPC. Methods Using RON‐modulated genetically engineered mouse models (GEMMs) and GEMM‐derived cell lines and co‐cultures with bone marrow‐derived macrophages, we show functional and molecular characteristics of signaling pathways in supporting CRPC. Further, we used an unbiased phosphokinase array to identify pathway interactions regulated by RON. Finally, using human prostate cancer cell lines and prostate cancer patient data sets, we show the relevance of our findings to human prostate cancer. Results Studies herein show that macrophages recruited into the prostate tumor microenvironment (TME) serve as a source for Gas6 secretion which serves to further enhance RON and Axl receptor activation in prostate tumor cells thereby driving CRPC. Further, we show targeting RON and macrophages in a murine model promotes CRPC sensitization to ADT. Conclusions We discovered a novel role for the RON receptor in prostate cancer cells in promoting CRPC through the recruitment of macrophages into the prostate TME. Macrophage‐targeting agents in combination with RON/Axl inhibition are likely to provide clinical benefits for patients with CRPC.