Androgen receptor pathway-independent prostate cancer is sustained through FGF signaling Journal Article
| Authors: | Bluemn, E. G.; Coleman, I. M.; Lucas, J. M.; Coleman, R. T.; Hernandez-Lopez, S.; Tharakan, R.; Bianchi-Frias, D.; Dumpit, R. F.; Kaipainen, A.; Corella, A. N.; Yang, Y. C.; Nyquist, M. D.; Mostaghel, E.; Hsieh, A. C.; Zhang, X.; Corey, E.; Brown, L. G.; Nguyen, H. M.; Pienta, K.; Ittmann, M.; Schweizer, M.; True, L. D.; Wise, D.; Rennie, P. S.; Vessella, R. L.; Morrissey, C.; Nelson, P. S. |
| Article Title: | Androgen receptor pathway-independent prostate cancer is sustained through FGF signaling |
| 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. © 2017 Elsevier Inc. |
| Keywords: | signal transduction; mitogen activated protein kinase; controlled study; human tissue; cancer growth; nonhuman; mouse; animal; animals; mice; animal tissue; metastasis; map kinase signaling system; inhibitor of differentiation 1; animal experiment; animal model; in vivo study; cell differentiation; in vitro study; pathology; enzyme activity; cell line, tumor; physiology; prostatic neoplasms; nucleotide sequence; tumor cell line; androgen antagonists; neoplasm metastasis; androgen receptor; inhibitor of differentiation protein 1; cancer tissue; antiandrogen; receptors, androgen; fibroblast growth factor; fibroblast growth factors; castration resistant prostate cancer; neuroendocrine; fgf; fibroblast growth factor receptor; id1; receptors, fibroblast growth factor; drug effects; castration-resistant prostate cancer; mapk signaling; humans; human; male; priority journal; article; id1 protein, human; lncap cell line; antagonists and inhibitors; androgen-pathway independence |
| Journal Title: | Cancer Cell |
| Volume: | 32 |
| Issue: | 4 |
| ISSN: | 1535-6108 |
| Publisher: | Cell Press |
| Date Published: | 2017-10-09 |
| Start Page: | 474 |
| End Page: | 489.e6 |
| Language: | English |
| DOI: | 10.1016/j.ccell.2017.09.003 |
| PUBMED: | 29017058 |
| PROVIDER: | scopus |
| PMCID: | PMC5750052 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 4 December 2017 -- Source: Scopus |
