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
Affiliations
Hira Lal Goel
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA
Bryan Pursell
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA
Leonard D. Shultz
The Jackson Laboratory, Bar Harbor, ME 04609, USA
Dale L. Greiner
Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
Rolf A. Brekken
Division of Surgical Oncology, Department of Surgery, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Craig W. Vander Kooi
Department of Cellular and Molecular Biochemistry, Center for Structural Biology, University of Kentucky, Lexington, KY 40506, USA
Arthur M. Mercurio
Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA
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.
