Activation of MAPK Signaling by CXCR7 leads to enzalutamide resistance in prostate cancer

Shangze Li, Ka Wing Fong, Galina Gritsina, Ali Zhang, Changsheng Zhao, Jung Kim, Adam Sharp, Wei Yuan, Caterina Aversa, Ximing J Yang, Peter S. Nelson, Felix Y. Feng, Arul M. Chinnaiyan, Johann S. De Bono, Colm Morrissey, Matthew B. Rettig, Jindan Yu*

*Corresponding author for this work

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Castration-resistant prostate cancer (CRPC) that has developed resistance to the new-generation androgen receptor (AR) antagonist enzalutamide is a lethal disease. Transcriptome analysis of multiple prostate cancer models identified CXCR7, an atypical chemokine receptor, as one of the most upregulated genes in enzalutamide-resistant cells. AR directly repressed CXCR7 by binding to an enhancer 110 kb downstream of the gene and expression was restored upon androgen deprivation. We demonstrate that CXCR7 is a critical regulator of prostate cancer sensitivity to enzalutamide and is required for CRPC growth in vitro and in vivo. Elevated CXCR7 activated MAPK/ERK signaling through ligand-independent, but β-arrestin 2-dependent mechanisms. Examination of patient specimens showed that CXCR7 and pERK levels increased significantly from localized prostate cancer to CRPC and further upon enzalutamide resistance. Preclinical studies revealed remarkable efficacies of MAPK/ERK inhibitors in suppressing enzalutamide- resistant prostate cancer. Overall, these results indicate that CXCR7 may serve as a biomarker of resistant disease in patients with prostate cancer and that disruption of CXCR7 signaling may be an effective strategy to overcome resistance. Significance: These findings identify CXCR7-mediated MAPK activation as a mechanism of resistance to secondgeneration antiandrogen therapy, highlighting the therapeutic potential of MAPK/ERK inhibitors in CRPC.

Original languageEnglish (US)
Pages (from-to)2580-2592
Number of pages13
JournalCancer Research
Volume79
Issue number10
DOIs
StatePublished - Jan 1 2019

Fingerprint

Prostatic Neoplasms
Castration
Androgen Receptor Antagonists
MDV 3100
Androgen Antagonists
Chemokine Receptors
Androgen Receptors
Gene Expression Profiling
Androgens
Biomarkers
Ligands
Gene Expression
Therapeutics
Growth
Genes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Li, Shangze ; Fong, Ka Wing ; Gritsina, Galina ; Zhang, Ali ; Zhao, Changsheng ; Kim, Jung ; Sharp, Adam ; Yuan, Wei ; Aversa, Caterina ; Yang, Ximing J ; Nelson, Peter S. ; Feng, Felix Y. ; Chinnaiyan, Arul M. ; De Bono, Johann S. ; Morrissey, Colm ; Rettig, Matthew B. ; Yu, Jindan. / Activation of MAPK Signaling by CXCR7 leads to enzalutamide resistance in prostate cancer. In: Cancer Research. 2019 ; Vol. 79, No. 10. pp. 2580-2592.
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title = "Activation of MAPK Signaling by CXCR7 leads to enzalutamide resistance in prostate cancer",
abstract = "Castration-resistant prostate cancer (CRPC) that has developed resistance to the new-generation androgen receptor (AR) antagonist enzalutamide is a lethal disease. Transcriptome analysis of multiple prostate cancer models identified CXCR7, an atypical chemokine receptor, as one of the most upregulated genes in enzalutamide-resistant cells. AR directly repressed CXCR7 by binding to an enhancer 110 kb downstream of the gene and expression was restored upon androgen deprivation. We demonstrate that CXCR7 is a critical regulator of prostate cancer sensitivity to enzalutamide and is required for CRPC growth in vitro and in vivo. Elevated CXCR7 activated MAPK/ERK signaling through ligand-independent, but β-arrestin 2-dependent mechanisms. Examination of patient specimens showed that CXCR7 and pERK levels increased significantly from localized prostate cancer to CRPC and further upon enzalutamide resistance. Preclinical studies revealed remarkable efficacies of MAPK/ERK inhibitors in suppressing enzalutamide- resistant prostate cancer. Overall, these results indicate that CXCR7 may serve as a biomarker of resistant disease in patients with prostate cancer and that disruption of CXCR7 signaling may be an effective strategy to overcome resistance. Significance: These findings identify CXCR7-mediated MAPK activation as a mechanism of resistance to secondgeneration antiandrogen therapy, highlighting the therapeutic potential of MAPK/ERK inhibitors in CRPC.",
author = "Shangze Li and Fong, {Ka Wing} and Galina Gritsina and Ali Zhang and Changsheng Zhao and Jung Kim and Adam Sharp and Wei Yuan and Caterina Aversa and Yang, {Ximing J} and Nelson, {Peter S.} and Feng, {Felix Y.} and Chinnaiyan, {Arul M.} and {De Bono}, {Johann S.} and Colm Morrissey and Rettig, {Matthew B.} and Jindan Yu",
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Li, S, Fong, KW, Gritsina, G, Zhang, A, Zhao, C, Kim, J, Sharp, A, Yuan, W, Aversa, C, Yang, XJ, Nelson, PS, Feng, FY, Chinnaiyan, AM, De Bono, JS, Morrissey, C, Rettig, MB & Yu, J 2019, 'Activation of MAPK Signaling by CXCR7 leads to enzalutamide resistance in prostate cancer', Cancer Research, vol. 79, no. 10, pp. 2580-2592. https://doi.org/10.1158/0008-5472.CAN-18-2812

Activation of MAPK Signaling by CXCR7 leads to enzalutamide resistance in prostate cancer. / Li, Shangze; Fong, Ka Wing; Gritsina, Galina; Zhang, Ali; Zhao, Changsheng; Kim, Jung; Sharp, Adam; Yuan, Wei; Aversa, Caterina; Yang, Ximing J; Nelson, Peter S.; Feng, Felix Y.; Chinnaiyan, Arul M.; De Bono, Johann S.; Morrissey, Colm; Rettig, Matthew B.; Yu, Jindan.

In: Cancer Research, Vol. 79, No. 10, 01.01.2019, p. 2580-2592.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Activation of MAPK Signaling by CXCR7 leads to enzalutamide resistance in prostate cancer

AU - Li, Shangze

AU - Fong, Ka Wing

AU - Gritsina, Galina

AU - Zhang, Ali

AU - Zhao, Changsheng

AU - Kim, Jung

AU - Sharp, Adam

AU - Yuan, Wei

AU - Aversa, Caterina

AU - Yang, Ximing J

AU - Nelson, Peter S.

AU - Feng, Felix Y.

AU - Chinnaiyan, Arul M.

AU - De Bono, Johann S.

AU - Morrissey, Colm

AU - Rettig, Matthew B.

AU - Yu, Jindan

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Castration-resistant prostate cancer (CRPC) that has developed resistance to the new-generation androgen receptor (AR) antagonist enzalutamide is a lethal disease. Transcriptome analysis of multiple prostate cancer models identified CXCR7, an atypical chemokine receptor, as one of the most upregulated genes in enzalutamide-resistant cells. AR directly repressed CXCR7 by binding to an enhancer 110 kb downstream of the gene and expression was restored upon androgen deprivation. We demonstrate that CXCR7 is a critical regulator of prostate cancer sensitivity to enzalutamide and is required for CRPC growth in vitro and in vivo. Elevated CXCR7 activated MAPK/ERK signaling through ligand-independent, but β-arrestin 2-dependent mechanisms. Examination of patient specimens showed that CXCR7 and pERK levels increased significantly from localized prostate cancer to CRPC and further upon enzalutamide resistance. Preclinical studies revealed remarkable efficacies of MAPK/ERK inhibitors in suppressing enzalutamide- resistant prostate cancer. Overall, these results indicate that CXCR7 may serve as a biomarker of resistant disease in patients with prostate cancer and that disruption of CXCR7 signaling may be an effective strategy to overcome resistance. Significance: These findings identify CXCR7-mediated MAPK activation as a mechanism of resistance to secondgeneration antiandrogen therapy, highlighting the therapeutic potential of MAPK/ERK inhibitors in CRPC.

AB - Castration-resistant prostate cancer (CRPC) that has developed resistance to the new-generation androgen receptor (AR) antagonist enzalutamide is a lethal disease. Transcriptome analysis of multiple prostate cancer models identified CXCR7, an atypical chemokine receptor, as one of the most upregulated genes in enzalutamide-resistant cells. AR directly repressed CXCR7 by binding to an enhancer 110 kb downstream of the gene and expression was restored upon androgen deprivation. We demonstrate that CXCR7 is a critical regulator of prostate cancer sensitivity to enzalutamide and is required for CRPC growth in vitro and in vivo. Elevated CXCR7 activated MAPK/ERK signaling through ligand-independent, but β-arrestin 2-dependent mechanisms. Examination of patient specimens showed that CXCR7 and pERK levels increased significantly from localized prostate cancer to CRPC and further upon enzalutamide resistance. Preclinical studies revealed remarkable efficacies of MAPK/ERK inhibitors in suppressing enzalutamide- resistant prostate cancer. Overall, these results indicate that CXCR7 may serve as a biomarker of resistant disease in patients with prostate cancer and that disruption of CXCR7 signaling may be an effective strategy to overcome resistance. Significance: These findings identify CXCR7-mediated MAPK activation as a mechanism of resistance to secondgeneration antiandrogen therapy, highlighting the therapeutic potential of MAPK/ERK inhibitors in CRPC.

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