Abstract:
:Androgen deprivation therapy and second-generation androgen receptor signaling inhibitors such as enzalutamide are standard treatments for advanced/metastatic prostate cancer. Unfortunately, most men develop resistance and relapse; signaling via insulin-like growth factor (IGF) has been implicated in castration-resistant prostate cancer. We evaluated the antitumor activity of xentuzumab (IGF ligand-neutralizing antibody), alone and in combination with enzalutamide, in prostate cancer cell lines (VCaP, DuCaP, MDA PCa 2b, LNCaP, and PC-3) using established in vitro assays, and in vivo, using LuCaP 96CR, a prostate cancer patient-derived xenograft (PDX) model. Xentuzumab + enzalutamide reduced the viability of phosphatase and tensin homolog (PTEN)-expressing VCaP, DuCaP, and MDA PCa 2b cells more than either single agent, and increased antiproliferative activity and apoptosis induction in VCaP. Xentuzumab or xentuzumab + enzalutamide inhibited IGF type 1 receptor and AKT serine/threonine kinase (AKT) phosphorylation in VCaP, DuCaP, and MDA PCa 2b cells; xentuzumab had no effect on AKT phosphorylation and proliferation in PTEN-null LNCaP or PC-3 cells. Knockdown of PTEN led to loss of antiproliferative activity of xentuzumab and reduced activity of xentuzumab + enzalutamide in VCaP cells. Xentuzumab + enzalutamide inhibited the growth of castration-resistant LuCaP 96CR PDX with acquired resistance to enzalutamide, and improved survival in vivo The data suggest that xentuzumab + enzalutamide combination therapy may overcome castration resistance and could be effective in patients who are resistant to enzalutamide alone. PTEN status as a biomarker of responsiveness to combination therapy needs further investigation.
journal_name
Mol Cancer Therjournal_title
Molecular cancer therapeuticsauthors
Weyer-Czernilofsky U,Hofmann MH,Friedbichler K,Baumgartinger R,Adam PJ,Solca F,Kraut N,Nguyen HM,Corey E,Liu G,Sprenger CC,Plymate SR,Bogenrieder Tdoi
10.1158/1535-7163.MCT-19-0378subject
Has Abstractpub_date
2020-04-01 00:00:00pages
1059-1069issue
4eissn
1535-7163issn
1538-8514pii
1535-7163.MCT-19-0378journal_volume
19pub_type
杂志文章abstract::The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that exists in two complexes (mTORC1 and mTORC2) and integrates extracellular and intracellular signals to act as a master regulator of cell growth, survival, and metabolism. The PI3K/AKT/mTOR prosurvival pathway is often dysregulated in mul...
journal_title:Molecular cancer therapeutics
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-12-0632
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-16-0207
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-06-0403
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-15-0052
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-05-0227
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-14-0046-T
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pub_type: 杂志文章
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
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journal_title:Molecular cancer therapeutics
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doi:10.1158/1535-7163.MCT-18-1385
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-06-0066
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pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-14-0354
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-18-0945
更新日期:2019-07-01 00:00:00
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-05-0064
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pub_type: 杂志文章
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journal_title:Molecular cancer therapeutics
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journal_title:Molecular cancer therapeutics
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journal_title:Molecular cancer therapeutics
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
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journal_title:Molecular cancer therapeutics
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journal_title:Molecular cancer therapeutics
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journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
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journal_title:Molecular cancer therapeutics
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journal_title:Molecular cancer therapeutics
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journal_title:Molecular cancer therapeutics
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journal_title:Molecular cancer therapeutics
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