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

doi:10.1016/j.celrep.2016.02.016

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

Cell Rep. 2016 Mar 8;14(9):2193-2208. doi: 10.1016/j.celrep.2016.02.016. Epub 2016 Feb 25.

Authors

Hira Lal Goel¹, Bryan Pursell², Leonard D Shultz³, Dale L Greiner⁴, Rolf A Brekken⁵, Craig W Vander Kooi⁶, Arthur M Mercurio⁷

Affiliations

¹ Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: [email protected].
² Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
³ The Jackson Laboratory, Bar Harbor, ME 04609, USA.
⁴ Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
⁵ Division of Surgical Oncology, Department of Surgery, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁶ Department of Cellular and Molecular Biochemistry, Center for Structural Biology, University of Kentucky, Lexington, KY 40506, USA.
⁷ Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA. Electronic address: [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adenocarcinoma / drug therapy
Adenocarcinoma / metabolism*
Angiogenesis Inhibitors / pharmacology
Animals
Bevacizumab / pharmacology
Carcinogenesis / metabolism
Cell Line, Tumor
Cell Survival / drug effects
Drug Resistance, Neoplasm*
Gene Expression Regulation, Neoplastic
Guanine Nucleotide Exchange Factors / physiology*
Humans
Indoles / pharmacology
Inhibitory Concentration 50
Male
Mice, Inbred NOD
Mice, SCID
Molecular Targeted Therapy
Neoplastic Stem Cells / drug effects
Neoplastic Stem Cells / physiology
Prostatic Neoplasms / drug therapy
Prostatic Neoplasms / metabolism*
Pyrroles / pharmacology
Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors
Sunitinib
Vascular Endothelial Growth Factor A / antagonists & inhibitors
Xenograft Model Antitumor Assays

Substances

Angiogenesis Inhibitors
Guanine Nucleotide Exchange Factors
Indoles
PREX1 protein, human
Pyrroles
VEGFA protein, human
Vascular Endothelial Growth Factor A
Bevacizumab
Receptors, Vascular Endothelial Growth Factor
Sunitinib

Abstract

Publication types

MeSH terms

Substances

Grants and funding