Journal
CANCER CELL
Volume 32, Issue 4, Pages 474-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2017.09.003
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Funding
- NIH [P50CA097186, P01 CA163227]
- DOD [PC140794, PC160662]
- DF/HCC
- Institute for Prostate Cancer Research
- Richard M. Lucas Foundation
- Movember
- Prostate Cancer Foundation
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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.
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