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Cancer-specific mutations in PIK3CA are oncogenic in vivo

Andreas G Bader1, Sohye Kang, Peter K Vogt

  • 1Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.

Proceedings of the National Academy of Sciences of the United States of America
|January 25, 2006
PubMed

Insights

Common PIK3CA gene mutations, leading to altered p110alpha proteins, drive tumor growth in vivo. These oncogenic PIK3CA mutants promote angiogenesis and Akt pathway activation, suggesting a key role in human cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • The PIK3CA gene encodes the p110alpha catalytic subunit of phosphatidylinositol 3-kinases (PI3Ks).
  • Mutations in PIK3CA are frequent in human cancers, and altered p110alpha proteins exhibit enhanced enzymatic activity and oncogenic potential in vitro and in cell culture.

Purpose of the Study:

  • To investigate the in vivo oncogenicity of prevalent PIK3CA mutants.
  • To determine the effects of these mutants on tumor development, angiogenesis, and downstream signaling pathways.
  • To evaluate the therapeutic potential of targeting PI3K/Akt pathway in PIK3CA-mutant driven cancers.

Main Methods:

  • Utilized a chicken embryo chorioallantoic membrane assay to assess in vivo oncogenicity.
  • Induced hemangiosarcomas in animals using specific PIK3CA mutants (E542K, E545K, H1047R).
  • Analyzed tumor characteristics including angiogenesis and Akt pathway activation.
  • Administered RAD001, a mTOR inhibitor, to evaluate its effect on tumor growth.

Main Results:

  • Three prevalent PIK3CA mutants (E542K, E545K, H1047R) demonstrated in vivo oncogenicity.
  • Tumors induced by these mutants exhibited increased angiogenesis and Akt pathway activation.
  • RAD001 treatment effectively blocked tumor growth driven by the H1047R PIK3CA mutant.

Conclusions:

  • The in vivo oncogenicity of PIK3CA mutants in an avian model strongly supports their critical role in human malignancies.
  • Targeting the PI3K/Akt pathway, potentially with mTOR inhibitors, is a viable strategy for treating cancers with these PIK3CA mutations.

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