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Pharmacological strategies to overcome HER2 cross-talk and Trastuzumab resistance

R Nahta1

  • 1Departments of Pharmacology, Emory University School of Medicine, USA. rnahta@emory.edu

Current Medicinal Chemistry
|January 11, 2012
PubMed

Insights

Trastuzumab resistance in HER2-positive breast cancer stems from cross-signaling pathways. Targeting these HER2 cross-talk mechanisms offers a promising strategy for treating refractory cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • HER2-overexpressing breast cancer affects 20-30% of patients.
  • Trastuzumab is an anti-HER2 antibody, but resistance is common.
  • Resistance mechanisms involve cross-signaling from other receptor tyrosine kinases.

Purpose of the Study:

  • To review molecular mechanisms of trastuzumab resistance in HER2-positive breast cancer.
  • To explore the role of HER2 cross-talk in acquired resistance.
  • To discuss targeting HER2 cross-talk as a therapeutic strategy.

Main Methods:

  • Literature review of molecular mechanisms.
  • Analysis of signaling pathways involved in resistance.
  • Discussion of pharmacological inhibition strategies.

Main Results:

  • Cross-signaling from HER/erbB family and other receptors contributes to resistance.
  • PI3K/mTOR and Src-FAK signaling pathways are key downstream mediators.
  • These pathways are implicated in both primary and acquired trastuzumab resistance.

Conclusions:

  • HER2 cross-talk is a significant driver of trastuzumab resistance.
  • Inhibiting these cross-talk pathways presents a viable therapeutic approach.
  • Targeting PI3K/mTOR and Src-FAK may overcome trastuzumab-refractory disease.

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