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Insulin-Mediated Signaling Facilitates Resistance to PDGFR Inhibition in Proneural hPDGFB-Driven Gliomas

Damian A Almiron Bonnin1,2, Cong Ran1,2, Matthew C Havrda1,2

  • 1Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.

Molecular Cancer Therapeutics
|February 1, 2017
PubMed

Insights

Therapeutic resistance in glioblastoma (GBM) involves insulin receptor (IR)/insulin growth-like factor receptor (IGF1R) signaling. Targeting IR/IGF1R alongside PDGFR may overcome resistance to receptor tyrosine kinase inhibitors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Receptor tyrosine kinases (RTKs), including platelet-derived growth factor receptor (PDGFR), are implicated in glioblastoma (GBM) pathogenesis.
  • Therapeutic resistance to RTK inhibitors is a major clinical challenge in treating GBM.

Purpose of the Study:

  • To investigate the mechanisms of therapeutic resistance in proneural gliomas driven by PDGFR signaling.
  • To identify alternative therapeutic targets to overcome resistance to PDGFR inhibition.

Main Methods:

  • Utilized a genetically engineered mouse model of proneural glioma that develops resistance to PDGFR inhibition.
  • Assessed the role of insulin receptor (IR)/insulin growth-like factor receptor (IGF1R) signaling in resistant tumor cells.
  • Evaluated the efficacy of cotargeting IR/IGF1R and PDGFR in vitro.

Main Results:

  • Tumors resistant to PDGFR inhibition showed dependence on IR/IGF1R signaling for proliferation and survival.
  • Cotargeting IR/IGF1R and PDGFR significantly reduced the emergence of resistant clones in vitro.

Conclusions:

  • The IR/IGF1R signaling axis is a key mediator of resistance to PDGFR inhibition in a subset of gliomas.
  • IR/IGF1R signaling is crucial for glioma recurrence, particularly in the proneural subtype.
  • Combined inhibition of IR/IGF1R and PDGFR presents a potential strategy to overcome therapeutic resistance in GBM.

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