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Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors

Anindita Chakrabarty1, Violeta Sánchez, María G Kuba

  • 1Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.

Proceedings of the National Academy of Sciences of the United States of America
|March 4, 2011
PubMed

Insights

PI3K inhibitors like XL147 show promise against breast cancer, but feedback mechanisms limit their effectiveness. Combining PI3K inhibitors with HER2/HER3 antagonists is crucial for HER2-overexpressing cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • The phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is frequently activated in human breast cancer.
  • Constitutive PI3K activation drives tumor growth and resistance to therapy.

Purpose of the Study:

  • To investigate the efficacy of the PI3K inhibitor XL147 in human breast cancer cell lines.
  • To elucidate the mechanisms of resistance to PI3K inhibition, particularly in HER2-overexpressing breast cancer.
  • To evaluate combination strategies involving PI3K inhibitors and HER2/HER3 antagonists.

Main Methods:

  • Treatment of human breast cancer cell lines with XL147.
  • Assessment of cell growth, pAKT, and pS6 levels.
  • Analysis of receptor tyrosine kinase (RTK) expression and phosphorylation.
  • Gene knockdown studies using small interfering RNA (siRNA) for FoxO1, FoxO3a, and HER3.
  • In vivo studies using BT474 xenografts.

Main Results:

  • XL147 demonstrated dose-dependent inhibition of cell growth, pAKT, and pS6.
  • PI3K inhibition led to upregulation of RTKs, including HER3, in HER2-overexpressing cells.
  • FoxO transcription factors mediated the induction of RTK mRNAs upon PI3K inhibition.
  • HER3 knockdown or HER2/HER3 antagonist cotreatment enhanced XL147-induced cell death and pathway inhibition.
  • Combination therapy with XL147 and HER2 inhibitors synergized in inhibiting pAKT and tumor growth in xenografts.

Conclusions:

  • PI3K antagonists inhibit AKT signaling but can trigger feedback mechanisms involving RTK upregulation.
  • This feedback limits sustained PI3K/AKT pathway inhibition and response to single-agent PI3K inhibitors.
  • Combination therapy with PI3K inhibitors and HER2/HER3 antagonists is a promising strategy for HER2-overexpressing breast cancer.

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