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

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 journal › Article › peer-review

47 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 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.

Original language	English (US)
Pages (from-to)	2193-2208
Number of pages	16
Journal	Cell Reports
Volume	14
Issue number	9
DOIs	https://doi.org/10.1016/j.celrep.2016.02.016
State	Published - Mar 8 2016

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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title = "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 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.",

author = "Goel, {Hira Lal} and Bryan Pursell and Shultz, {Leonard D.} and Greiner, {Dale L.} and Brekken, {Rolf A.} and {Vander Kooi}, {Craig W.} and Mercurio, {Arthur M.}",

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AU - Pursell, Bryan

AU - Shultz, Leonard D.

AU - Greiner, Dale L.

AU - Brekken, Rolf A.

AU - Vander Kooi, Craig W.

AU - Mercurio, Arthur M.

PY - 2016/3/8

Y1 - 2016/3/8

N2 - 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.

AB - 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.

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

Abstract

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