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The brain microenvironment mediates resistance in luminal breast cancer to PI3K inhibition through HER3 activation

David P Kodack1, Vasileios Askoxylakis1, Gino B Ferraro1

  • 1Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital (MGH) and Harvard Medical School (HMS), Boston, MA 02114, USA.

Science Translational Medicine
|May 26, 2017
PubMed

Insights

Brain metastases in breast cancer resist PI3K inhibitors due to increased HER3 signaling. Blocking HER3 overcomes this resistance, offering new treatment strategies for brain metastases.

Area of Science:

  • Oncology
  • Cancer Biology
  • Pharmacology

Background:

  • Targeted therapies often show limited efficacy against brain metastases.
  • Breast cancer brain metastases can evade phosphatidylinositide 3-kinase (PI3K) inhibition despite adequate drug levels.
  • Understanding resistance mechanisms in the brain microenvironment is crucial for effective treatment.

Purpose of the Study:

  • To investigate the mechanisms of resistance to PI3K inhibitors in breast cancer brain metastases.
  • To identify therapeutic strategies to overcome resistance in HER2-amplified and/or PIK3CA-mutant breast cancer brain metastases.

Main Methods:

  • Utilized preclinical models of breast cancer brain metastases.
  • Analyzed HER3 expression and phosphorylation in brain lesions compared to extracranial disease.
  • Evaluated the efficacy of combined PI3K and HER3 inhibition.

Main Results:

  • Brain metastases exhibited increased HER3 expression and phosphorylation compared to extracranial tumors.
  • HER3 blockade in combination with PI3K inhibitors overcame resistance in preclinical models.
  • Combined therapy resulted in significant tumor growth delay and improved survival in mice.

Conclusions:

  • Increased HER3 signaling is a key mechanism of resistance to PI3K inhibitors in breast cancer brain metastases.
  • Targeting HER3 in conjunction with PI3K inhibitors represents a promising therapeutic strategy.
  • These findings provide a rationale for clinical trials investigating combination therapies for brain metastases.

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