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Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways

Siyuan Zhang1, Wen-Chien Huang, Ping Li

  • 1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Nature Medicine
|March 15, 2011
PubMed

Insights

Trastuzumab resistance in ERBB2-positive breast cancer is linked to activated c-SRC (SRC). Targeting SRC with trastuzumab overcomes resistance and eliminates tumors, offering a new clinical strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapy

Background:

  • Trastuzumab is an ERBB2-targeted therapy for breast cancer.
  • Many patients develop resistance to trastuzumab due to various mechanisms.
  • Effective treatments to overcome trastuzumab resistance are needed.

Purpose of the Study:

  • To identify key modulators of trastuzumab resistance.
  • To investigate the role of c-SRC (SRC) in trastuzumab resistance pathways.
  • To evaluate SRC inhibition as a strategy to overcome trastuzumab resistance.

Main Methods:

  • Analysis of SRC activation in trastuzumab-resistant breast cancer cells (acquired and de novo).
  • Investigation of SRC regulation by PTEN.
  • In vitro and in vivo studies combining SRC inhibitors with trastuzumab.

Main Results:

  • SRC is activated in trastuzumab-resistant cells and is a common node in resistance pathways.
  • A novel PTEN-mediated dephosphorylation mechanism regulates SRC.
  • Combined SRC and trastuzumab therapy sensitized resistant cells and eradicated tumors in vivo.

Conclusions:

  • SRC activation is a critical factor in trastuzumab resistance.
  • Targeting SRC in combination with trastuzumab is a promising strategy to overcome resistance in ERBB2-positive breast cancer.
  • This approach has potential clinical applications for resistant breast cancer patients.

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