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, Nelson Peter S
Department of Medicine, University of Washington, Seattle, WA, USA; Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Mailstop D4-100, 1100 Fairview Avenue N, Seattle, WA 98109-1024, USA.
Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Mailstop D4-100, 1100 Fairview Avenue N, Seattle, WA 98109-1024, USA.
Cancer Cell. 2017 Oct 9;32(4):474-489.e6. doi: 10.1016/j.ccell.2017.09.003.
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.
雄激素受体（AR）信号传导是前列腺癌（PC）的一个显著特征，也是治疗转移性前列腺癌（mPC）的主要治疗靶点。尽管AR拮抗作用非常有效，但它会导致肿瘤绕过对AR的功能需求，通常是通过神经内分泌（NE）转分化实现的。通过对二十多年来mPC的分子评估，我们发现mPC出现了一种表型转变，即出现了AR缺失NE缺失的表型。这些“双阴性”PC的显著特点是FGF和MAPK信号通路活性升高，这可以绕过对AR的依赖。MAPK或FGFR的药理抑制剂在体外和体内均能抑制双阴性PC的生长。我们的结果表明，FGF/MAPK阻断可能对具有AR缺失表型的mPC特别有效。
