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The PDGFRβ-AKT pathway contributes to CDDP-acquired resistance in testicular germ cell tumors

M Juliachs1, C Muñoz, C A Moutinho

  • 1Authors' Affiliations: Laboratori de Recerca Translacional and Servei d'Oncologia Mèdica, Institut Català d'Oncologia, Hospital Duran i Reynals; Servei d'Anatomia Patològica, Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat; Departaments de Patologia i Terapèutica Experimental and Ciències Fisiològiques II, Universitat de Barcelona; Institut d'Investigació Biomèdica de Bellvitge (IDIBELL); Laboratori d'Oncologia Molecular and Cancer Epigenetics and Biology Program (PEBC), Institut d'Investigació Biomèdica de Bellvitge (IDIBELL); Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|November 27, 2013
PubMed
Abstract

Insights

Platelet-derived growth factor receptor beta (PDGFRβ) and AKT signaling drive cisplatin resistance in testicular germ cell tumors. Inhibiting this pathway resensitizes resistant cells to chemotherapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Cisplatin (CDDP) is a cornerstone chemotherapy for testicular germ cell tumors (TGTs).
  • Development of CDDP resistance in TGTs remains a significant clinical challenge.
  • Understanding the molecular mechanisms underlying CDDP resistance is crucial for improving treatment outcomes.

Purpose of the Study:

  • To investigate the roles of phosphoinositide 3-kinase-AKT (PI3K-AKT) and extracellular signal-regulated kinase (ERK) signaling pathways in CDDP resistance in TGT cells.
  • To identify key molecular targets for overcoming CDDP resistance in TGTs.

Main Methods:

  • Comparative analysis of AKT and ERK activation in CDDP-sensitive versus CDDP-resistant TGT cells.
  • Assessment of signaling pathways in orthotopic TGT models and human patient samples.
  • Manipulation of platelet-derived growth factor receptor beta (PDGFRβ) levels using short hairpin RNA (shRNA) and blockade of its activation with pazopanib.

Main Results:

  • Overactivation of AKT, but not ERK, was observed in CDDP-resistant TGT cells.
  • Increased messenger RNA (mRNA) and protein levels of PDGFRβ and its ligand PDGF-B were responsible for AKT overactivation.
  • Downregulation of PDGFRβ or blockade of its activation rendered CDDP-resistant cells sensitive to CDDP, and these cells showed increased sensitivity to PDGFRβ inhibitors.

Conclusions:

  • The PDGFRβ-AKT signaling pathway is critically involved in the development of CDDP resistance in TGT cells.
  • Targeting the PDGFRβ-AKT pathway represents a potential therapeutic strategy to overcome CDDP resistance in TGTs.
  • Overexpression of PDGFRβ and phosphorylated AKT (pAKT) in CDDP-resistant tumors highlights their clinical relevance.

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