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Platelet-derived growth factor/vascular endothelial growth factor receptor inactivation by sunitinib results in

Tram Anh Tran1, Lisa Kinch, Samuel Peña-Llopis

  • 1Department of Developmental Biology.

Molecular and Cellular Biology
|July 24, 2013
PubMed

Insights

Drosophila PVR, a PDGF/VEGF receptor, regulates TORC1 and ERK activity, impacting cell survival and tumor formation. Sunitinib, a cancer drug, inhibits PVR and TORC1, offering insights into drug resistance mechanisms.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Signal Transduction

Background:

  • Vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors are crucial in development and cancer.
  • Dual inhibitors like sunitinib target these receptors in cancer therapy.
  • Drosophila possesses a single ancestral PDGF/VEGF receptor, PVR, unlike mammals.

Purpose of the Study:

  • To identify novel regulators of target of rapamycin complex 1 (TORC1) in Drosophila.
  • To investigate the role of PVR in cellular signaling and tumor development.
  • To explore the mechanism of action of sunitinib in relation to PVR and TORC1.

Main Methods:

  • Unbiased RNA interference (RNAi) screen of Drosophila kinases and phosphatases.
  • Cell-based assays to measure TORC1 and ERK activity.
  • In vivo studies of hemocyte expansion and tumor-like structure formation.
  • Pharmacological inhibition using sunitinib in both insect and human cells.

Main Results:

  • PVR was identified as a novel regulator of TORC1 and ERK activity.
  • PVR is essential for cell survival in vitro and hemocyte expansion in vivo.
  • Constitutive PVR activation leads to tumor-like structures with high TORC1 activity.
  • Sunitinib inhibits PVR and TORC1 in insect cells, and TORC1 in human endothelial cells, dependent on the Tsc1/Tsc2 complex.

Conclusions:

  • PVR plays a critical role in maintaining TORC1 and ERK signaling, cell survival, and preventing tumor formation.
  • Sunitinib's inhibition of TORC1 is conserved across species and dependent on the Tsc1/Tsc2 complex.
  • Understanding PVR's mechanism offers insights into sunitinib's efficacy and resistance in cancer treatment.

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