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

Hira Lal Goel, Bryan Pursell, Leonard D. Shultz, Dale L. Greiner, Rolf A. Brekken, Craig W. Vander Kooi, Arthur M. Mercurio

Research output: Contribution to journalArticle

21 Scopus citations

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 PTENpc-/- 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.

Original languageEnglish (US)
Pages (from-to)2193-2208
Number of pages16
JournalCell Reports
Volume14
Issue number9
DOIs
StatePublished - Mar 8 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Goel, H. L., Pursell, B., Shultz, L. D., Greiner, D. L., Brekken, R. A., Vander Kooi, C. W., & Mercurio, A. M. (2016). P-Rex1 Promotes Resistance to VEGF/VEGFR-Targeted Therapy in Prostate Cancer. Cell Reports, 14(9), 2193-2208. https://doi.org/10.1016/j.celrep.2016.02.016