Androgen receptor (AR) signaling is a distinctive feature of prostate cancer (PC) and represents the major therapeutic target for the treatment of metastatic disease. Though highly effective, AR antagonism has the potential to generate tumors that bypass a functional requirement for AR activity. We show here that a phenotypic shift has occurred in metastatic PCs with the emer-gence of a double-negative AR-null neuroendocrine-null phenotype that is notable for MAPK and FGF pathway activity. To identify mechanisms capable of sustaining PC survival, we gener-ated a model system designated AR program-independent prostate cancer (APIPC) which re-sists AR-targeted therapeutics, lacks neuroendocrine features, expresses high levels of FGF8 and the ID1 oncogene, and activates MAPK signaling. Pharmacological blockade of MAPK or FGF signaling inhibited APIPC tumor growth, supporting FGF/MAPK as a therapeutic avenue for treating AR-null PC. SOURCE: Ilsa Coleman (icoleman@fhcrc.org) - Peter Nelson Fred Hutchinson Cancer Research Center

Pluto Bioinformatics

GSE99381: AR-independent prostate cancer is sustained through FGF signaling