RT Journal Article
SR Electronic
T1 Targeting cellular heterogeneity with CXCR2 blockade for the treatment of therapy-resistant prostate cancer
JF Science Translational Medicine
FD American Association for the Advancement of Science
SP eaax0428
DO 10.1126/scitranslmed.aax0428
VO 11
IS 521
A1 Li, Yanjing
A1 He, Yiping
A1 Butler, William
A1 Xu, Lingfan
A1 Chang, Yan
A1 Lei, Kefeng
A1 Zhang, Hong
A1 Zhou, Yinglu
A1 Gao, Allen C.
A1 Zhang, Qingfu
A1 Taylor, Daniel G.
A1 Cheng, Donghui
A1 Farber-Katz, Suzette
A1 Karam, Rachid
A1 Landrith, Tyler
A1 Li, Bing
A1 Wu, Sitao
A1 Hsuan, Vickie
A1 Yang, Qing
A1 Hu, Hailiang
A1 Chen, Xufeng
A1 Flowers, Melissa
A1 McCall, Shannon J.
A1 Lee, John K.
A1 Smith, Bryan A.
A1 Park, Jung Wook
A1 Goldstein, Andrew S.
A1 Witte, Owen N.
A1 Wang, Qianben
A1 Rettig, Matthew B.
A1 Armstrong, Andrew J.
A1 Cheng, Qing
A1 Huang, Jiaoti
YR 2019
UL http://stm.sciencemag.org/content/11/521/eaax0428.abstract
AB Treatments targeting the androgen receptor, a mainstay of prostate cancer therapy, do not usually cure the disease and eventually lose their effectiveness. A major cause of this therapeutic resistance is the presence of neuroendocrine tumor cells, which are not sensitive to androgen inhibition. Li et al. determined that neuroendocrine prostate cancer cells express a chemokine receptor called CXCR2 and showed that it can be used to help identify these cells in tumors and also plays a functional role in their resistance to treatment, making it a viable therapeutic target.Hormonal therapy targeting androgen receptor (AR) is initially effective to treat prostate cancer (PCa), but it eventually fails. It has been hypothesized that cellular heterogeneity of PCa, consisting of AR+ luminal tumor cells and AR− neuroendocrine (NE) tumor cells, may contribute to therapy failure. Here, we describe the successful purification of NE cells from primary fresh human prostate adenocarcinoma based on the cell surface receptor C-X-C motif chemokine receptor 2 (CXCR2). Functional studies revealed CXCR2 to be a driver of the NE phenotype, including loss of AR expression, lineage plasticity, and resistance to hormonal therapy. CXCR2-driven NE cells were critical for the tumor microenvironment by providing a survival niche for the AR+ luminal cells. We demonstrate that the combination of CXCR2 inhibition and AR targeting is an effective treatment strategy in mouse xenograft models. Such a strategy has the potential to overcome therapy resistance caused by tumor cell heterogeneity.