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P-Rex1 Promotes Resistance to VEGF/VEGFR-Targeted Therapy in Prostate Cancer.

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.

SUBMITTER: Goel HL 

PROVIDER: S-EPMC4791963 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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P-Rex1 Promotes Resistance to VEGF/VEGFR-Targeted Therapy in Prostate Cancer.

Goel Hira Lal HL   Pursell Bryan B   Shultz Leonard D LD   Greiner Dale L DL   Brekken Rolf A RA   Vander Kooi Craig W CW   Mercurio Arthur M AM  

Cell reports 20160225 9

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 induct  ...[more]

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