| Literature DB >> 26923603 |
Hira Lal Goel1, Bryan Pursell2, Leonard D Shultz3, Dale L Greiner4, Rolf A Brekken5, Craig W Vander Kooi6, Arthur M Mercurio7.
Abstract
Autocrine VEGF signaling is critical for sustaining prostate and other cancer stem cells (CSCs), and it is a potential therapeutic target, but we observed that CSCs isolated from prostate tumors are resistant to anti-VEGF (bevacizumab) and anti-VEGFR (sunitinib) therapy. Intriguingly, resistance is mediated by VEGF/neuropilin signaling, which is not inhibited by bevacizumab and sunitinib, and it involves the induction of P-Rex1, a Rac GEF, and consequent Rac1-mediated ERK activation. This induction of P-Rex1 is dependent on Myc. CSCs isolated from the PTEN(pc-/-) transgenic model of prostate cancer exhibit Rac1-dependent resistance to bevacizumab. Rac1 inhibition or P-Rex1 downregulation increases the sensitivity of prostate tumors to bevacizumab. These data reveal that prostate tumors harbor cells with stem cell properties that are resistant to inhibitors of VEGF/VEGFR signaling. Combining the use of available VEGF/VEGFR-targeted therapies with P-Rex1 or Rac1 inhibition should improve the efficacy of these therapies significantly.Entities:
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Year: 2016 PMID： 26923603 PMCID： PMC4791963 DOI： 10.1016/j.celrep.2016.02.016
Source DB: PubMed Journal: Cell Rep Impact factor: 9.423