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Insulin receptor functionally enhances multistage tumor progression and conveys intrinsic resistance to IGF-1R

Danielle B Ulanet1, Dale L Ludwig, C Ronald Kahn

  • 1Department of Biochemistry and Biophysics, Diabetes Center, University of California, San Francisco, CA 94143, USA.

Proceedings of the National Academy of Sciences of the United States of America
|May 12, 2010
PubMed

Insights

Insulin receptor (IR) signaling promotes pancreatic cancer growth and resistance to IGF-1R inhibitors. Targeting IR alongside IGF-1R may improve cancer therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Endocrinology

Background:

  • Type 1 insulin-like growth factor receptor (IGF-1R) signaling promotes tumor growth.
  • The homologous insulin receptor (IR) also conveys protumorigenic signals, but its role in cancer progression is not well-defined.
  • IR signaling may compromise the efficacy of IGF-1R-targeted cancer therapies.

Purpose of the Study:

  • To genetically define the role of IR in cancer progression in vivo.
  • To investigate whether IR signaling compromises the efficacy of IGF-1R inhibitors.
  • To explore IR as a potential therapeutic target in combination with IGF-1R inhibition.

Main Methods:

  • A transgenic mouse model of pancreatic neuroendocrine cancer.
  • Genetic disruption of the insulin receptor (IR) gene in oncogene-expressing pancreatic beta cells.
  • Preclinical trials using an inhibitory monoclonal antibody to IGF-1R.
  • Analysis of IR and IGF-1R expression in human breast cancer cells.

Main Results:

  • IGF-1R overexpression accelerated tumor progression in a mouse model.
  • IR levels were significantly upregulated during pancreatic islet tumor progression.
  • Genetic disruption of IR reduced tumor burden and increased apoptosis.
  • IR knockout tumors became sensitive to anti-IGF-1R therapy.
  • High IR to IGF-1R ratios conferred resistance to IGF-1R inhibition in human breast cancer cells.

Conclusions:

  • Elevated IR signaling contributes to pancreatic cancer progression.
  • IR signaling confers intrinsic and adaptive resistance to IGF-1R inhibitors.
  • Targeting IR may be a viable strategy to overcome resistance to IGF-1R-targeted therapies.

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