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.

中文翻译：

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雄激素受体途径无关的前列腺癌通过FGF信号传导得以维持。

雄激素受体（AR）信号传导是前列腺癌（PC）的显着特征，并且代表了治疗转移性前列腺癌（mPC）的主要治疗靶标。尽管非常有效，但AR拮抗作用通常会通过神经内分泌（NE）转分化作用而产生绕过AR功能要求的肿瘤。通过对二十多年来对mPC的分子评估，我们发现随着AR空NE型空表型的出现，mPC中发生了表型转变。这些“双重阴性”的PC以FGF和MAPK途径活性升高而著称，可以绕过AR依赖性。MAPK或FGFR的药理抑制剂在体外和体内均可抑制双重阴性PC的生长。我们的结果表明，FGF / MAPK阻断剂对具有AR空表型的mPC可能特别有效。