Open AccessP-Rex1 Promotes Resistance to VEGF/VEGFR-Targeted Therapy in Prostate Cancer
Author(s) -
Hira Lal Goel,
Bryan Pursell,
Leonard D. Shultz,
Dale L. Greiner,
Rolf A. Brekken,
Craig W. Vander Kooi,
Arthur M. Mercurio
Publication year - 2016
Publication title -
cell reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.264
H-Index - 154
eISSN - 2639-1856
pISSN - 2211-1247
DOI - 10.1016/j.celrep.2016.02.016
Subject(s) - bevacizumab , prostate cancer , cancer research , medicine , autocrine signalling , rac1 , sunitinib , cancer stem cell , cancer , biology , signal transduction , microbiology and biotechnology , receptor , chemotherapy
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.
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