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 language | English |
|---|---|
| Pages (from-to) | 2193-2208 |
| Number of pages | 16 |
| Journal | Cell Reports |
| Volume | 14 |
| Issue number | 9 |
| DOIs | |
| State | Published - Mar 8 2016 |
Bibliographical note
Publisher Copyright:© 2016 The Authors.
Funding
Work in the authors’ laboratory is supported by NIH grants CA168464 and CA159856 and by US Department of Defense prostate cancer grant W81XWH-12-1-0308 (A.M.M.), RO1GM094155 (C.W.V.K.), and Cancer Core grant CA034196 to the Jackson Laboratory (to L.D.S.). We thank Michael Lee for constructive comments on the manuscript. We also acknowledge the UMASS Medical School Cancer Center Tissue Bank for providing fresh tissue specimens and Dr. Chung-Cheng Hsieh for statistical analysis. Tissue microarrays containing prostate cancer tissues were kindly provided by Rosina Lis and Massimo Loda (Dana-Farber Cancer Institute). DNA constructs provided by other investigators are acknowledged in Experimental Procedures. We thank Dr. Hou-Fu Guo for the plate-based inhibition data and Dr. Yaping Tu for the P-Rex1 promoter construct. D.L.G. is a consultant for the Jackson Laboratory. R.A.B. has a commercial research grant from Peregrine Pharmaceuticals as well as other commercial research support from Affitech and is a consultant/advisory board member of Peregrine Pharmaceuticals.
| Funders | Funder number |
|---|---|
| Cancer Center Core | CA034196 |
| US Department of Defense | RO1GM094155, W81XWH-12-1-0308 |
| National Institutes of Health (NIH) | CA168464 |
| National Childhood Cancer Registry – National Cancer Institute | R01CA159856 |
| Jackson Laboratory | |
| Peregrine Pharmaceuticals Inc. |
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology
