Androgen Receptor Pathway-Independent Prostate Cancer Is Sustained through FGF Signaling

作者：Bluemn, Eric G.; Coleman, Ilsa M.; Lucas, Jared M.; Coleman, Roger T.; Hernandez-Lopez, Susana; Tharakan, Robin; Bianchi-Frias, Daniella; Dumpit, Ruth F.; Kaipainen, Arja; Corella, Alexandra N.; Yang, Yu Chi; Nyquist, Michael D.; Mostaghel, Elahe; Hsieh, Andrew C.; Zhang, Xiaotun; Corey, Eva; Brown, Lisha G.; Nguyen, Holly M.; Pienta, Kenneth; Ittmann, Michael; Schweizer, Michael; True, Lawrence D.; Wise, David; Rennie, Paul S.; Vessella, Robert L.; Morrissey, Colm^*

来源：Cancer Cell, 2017, 32(4): 474-+.

DOI：10.1016/j.ccell.2017.09.003

• SMALL-CELL CARCINOMA
• LINEAGE PLASTICITY
• INCREASED SURVIVAL
• MOUSE MODEL
• IN-VIVO
• ACTIVATION
• IDENTIFICATION
• METASTASIS
• RESISTANCE
• EXPRESSION

Androgen receptor (AR) signaling is a distinctive feature of prostate carcinoma (PC) and represents the major therapeutic target for treating metastatic prostate cancer (mPC). Though highly effective, AR antagonism can produce tumors that bypass a functional requirement for AR, often through neuroendocrine (NE) transdifferentiation. Through the molecular assessment of mPCs over two decades, we find a phenotypic shift has occurred in mPC with the emergence of an AR-null NE-null phenotype. These "double-negative'' PCs are notable for elevated FGF and MAPK pathway activity, which can bypass AR dependence. Pharmacological inhibitors of MAPK or FGFR repressed the growth of double-negative PCs in vitro and in vivo. Our results indicate that FGF/MAPK blockade may be particularly efficacious against mPCs with an AR-null phenotype.

• 出版日期2017-10-9