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Association between gain-of-function mutations in PIK3CA and resistance to HER2-targeted agents in HER2-amplified

Y Kataoka1, T Mukohara2, H Shimada3

  • 1Hospital Pharmacy.

Annals of Oncology : Official Journal of the European Society for Medical Oncology
|July 28, 2009
PubMed
Abstract

Insights

PIK3CA mutations confer resistance to HER2-targeted therapies in breast cancer. PI3K inhibitors may overcome this resistance, with S6K phosphorylation as a potential biomarker for treatment effectiveness.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Mechanisms of resistance to human epidermal growth factor receptor 2 (HER2)-targeted agents remain unclear.
  • Investigated the role of PIK3CA mutations in breast cancer cell line sensitivity to HER2-targeted therapies.

Purpose of the Study:

  • To determine the influence of PIK3CA mutations on sensitivity to HER2-targeted agents.
  • To evaluate the potential of PI3K inhibitors in overcoming resistance.

Main Methods:

  • Assessed effects of CL-387,785 (HER2 tyrosine kinase inhibitor) and trastuzumab on cell growth and signaling.
  • Utilized eight HER2-amplified breast cancer cell lines and trastuzumab-conditioned BT474 (BT474-TR).

Main Results:

  • PIK3CA-mutant cell lines showed increased resistance to trastuzumab and CL-387,785 compared to PIK3CA-wild-type lines.
  • CL-387,785 retained activity against BT474-TR cells.
  • Growth inhibition correlated strongly with S6K phosphorylation changes.

Conclusions:

  • PIK3CA mutations are linked to resistance against HER2-targeted agents.
  • PI3K inhibitors show promise for overcoming trastuzumab resistance driven by PIK3CA mutations.
  • S6K phosphorylation may serve as a pharmacodynamic marker in HER2-targeted therapy.

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