Abstract
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. Bluemn et al. show that androgen receptor (AR) inhibition results in a phenotypic shift in castration-resistant prostate cancer, leading to tumors that are AR-null but not neuroendocrine (NE). Models for AR-null, non-NE tumors show elevated FGF and MAPK activity and are sensitive to blockade of these pathways.
Original language | English (US) |
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Pages (from-to) | 474-489.e6 |
Journal | Cancer cell |
Volume | 32 |
Issue number | 4 |
DOIs | |
State | Published - Oct 9 2017 |
Keywords
- FGF
- ID1
- androgen-pathway independence
- castration-resistant prostate cancer
- neuroendocrine
ASJC Scopus subject areas
- Oncology
- Cancer Research