Dual inhibition using cabozantinib overcomes HGF/MET signaling mediated resistance to pan-VEGFR inhibition in orthotopic and metastatic neuroblastoma tumors

  • Authors:
    • Estelle Daudigeos-Dubus
    • Ludivine Le Dret
    • Olivia Bawa
    • Paule Opolon
    • Albane Vievard
    • Irène Villa
    • Jacques Bosq
    • Gilles Vassal
    • Birgit Geoerger
  • View Affiliations

  • Published online on: December 6, 2016     https://doi.org/10.3892/ijo.2016.3792
  • Pages: 203-211
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Abstract

MET is expressed on neuroblastoma cells and may trigger tumor growth, neoangiogenesis and metastasis. MET upregulation further represents an escape mechanism to various anticancer treatments including VEGF signaling inhibitors. We developed in vitro a resistance model to pan-VEGFR inhibition and explored the simultaneous inhibition of VEGFR and MET in neuroblastoma models in vitro and in vivo using cabozantinib, an inhibitor of the tyrosine kinases including VEGFR2, MET, AXL and RET. Resistance in IGR-N91-Luc neuroblastoma cells under continuous in vitro exposure pressure to VEGFR1-3 inhibition using axitinib was associated with HGF and p-ERK overexpression. Cabozantinib exhibited anti-proliferative effects in neuroblastoma cells and reduced cell migration in vitro as measured by phase-contrast with IncuCyte system. In vivo, an enhanced number of animals with IGR-N91-Luc metastases was noted following axitinib treatment as compared to control animals. Orally administered cabozantinib per gavage at 30 and 60 mg/kg/day significantly inhibited tumor growth of orthotopic adrenal IGR-N91-Luc and metastatic IMR-32-Luc xenografts. Antitumor activity was associated with decreased vascularization, inhibition of p-SRC and induction of apoptotic cell death. Activation of the HGF-mediated MET pathway is involved in escape to selective VEGFR inhibition in neuroblastoma suggesting combined inhibition of MET and VEGFR signaling to reduce secondary resistance and enhanced invasiveness.
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January-2017
Volume 50 Issue 1

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Daudigeos-Dubus E, Le Dret L, Bawa O, Opolon P, Vievard A, Villa I, Bosq J, Vassal G and Geoerger B: Dual inhibition using cabozantinib overcomes HGF/MET signaling mediated resistance to pan-VEGFR inhibition in orthotopic and metastatic neuroblastoma tumors. Int J Oncol 50: 203-211, 2017
APA
Daudigeos-Dubus, E., Le Dret, L., Bawa, O., Opolon, P., Vievard, A., Villa, I. ... Geoerger, B. (2017). Dual inhibition using cabozantinib overcomes HGF/MET signaling mediated resistance to pan-VEGFR inhibition in orthotopic and metastatic neuroblastoma tumors. International Journal of Oncology, 50, 203-211. https://doi.org/10.3892/ijo.2016.3792
MLA
Daudigeos-Dubus, E., Le Dret, L., Bawa, O., Opolon, P., Vievard, A., Villa, I., Bosq, J., Vassal, G., Geoerger, B."Dual inhibition using cabozantinib overcomes HGF/MET signaling mediated resistance to pan-VEGFR inhibition in orthotopic and metastatic neuroblastoma tumors". International Journal of Oncology 50.1 (2017): 203-211.
Chicago
Daudigeos-Dubus, E., Le Dret, L., Bawa, O., Opolon, P., Vievard, A., Villa, I., Bosq, J., Vassal, G., Geoerger, B."Dual inhibition using cabozantinib overcomes HGF/MET signaling mediated resistance to pan-VEGFR inhibition in orthotopic and metastatic neuroblastoma tumors". International Journal of Oncology 50, no. 1 (2017): 203-211. https://doi.org/10.3892/ijo.2016.3792