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Effective treatment of HER2-amplified breast cancer by targeting HER3 and β1 integrin
Marcia R Campbell1, Hui Zhang2, Shabnam Ziaee2
1Departments of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, UCSF Box 1387, San Francisco, CA, 94143, USA.
Abstract:
The central role of HER2 as the disease driver and HER3 as its essential partner has made them rational targets for the treatment of HER2-amplifed breast cancers, and there is considerable interest in developing highly effective treatment regimens for this disease that consist of targeted therapies alone. Much of these efforts are focused on dual targeting approaches, particularly dual targeting of the HER2-HER3 tumor driver complex itself, or vertical combinations that target downstream PI3K or Akt in addition to HER2. There is also potential in lateral combinations based on evidence implicating cross-talk with other membrane receptor systems, particularly integrins, and such lateral combinations can potentially involve either HER2 or HER3. We established a preclinical model of targeting HER3 using doxycycline-inducible shRNA and determined the efficacy of a β1 integrin inhibitor in combination with targeting HER3. We report that targeting HER3 and β1 integrin provides a particularly effective combination therapy approach for HER2-amplified cancers, surpassing the combination of HER2 and β1 integrin targeting, and evading some of the safety concerns associated with direct HER2-targeting. This further validates HER3 as a major hub mediating the tumorigenic functions of HER2 and identifies it as a high value target for lateral combination therapy strategies.
Insights
Targeting HER3 alongside β1 integrin shows promise for HER2-amplified breast cancers. This combination therapy is effective and may avoid safety concerns linked to direct HER2 targeting.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- HER2 is a key driver in HER2-amplified breast cancers, with HER3 as its crucial partner.
- Targeted therapies, especially dual-targeting approaches, are of significant interest for treating these cancers.
- Combinations targeting the HER2-HER3 complex, downstream pathways (PI3K/Akt), or involving cross-talk with other receptors like integrins are being explored.
Purpose of the Study:
- To investigate the efficacy of targeting HER3 in combination with a β1 integrin inhibitor.
- To evaluate this combination therapy in a preclinical model of HER2-amplified breast cancer.
- To compare the efficacy and safety of targeting HER3 plus β1 integrin versus targeting HER2 plus β1 integrin.
Main Methods:
- Established a preclinical model using doxycycline-inducible shRNA to target HER3.
- Administered a β1 integrin inhibitor in combination with HER3 targeting.
- Assessed the therapeutic efficacy of the combination therapy.
Main Results:
- Targeting HER3 and β1 integrin demonstrated a highly effective combination therapy for HER2-amplified cancers.
- This dual-targeting strategy proved superior to combining HER2 and β1 integrin inhibition.
- The HER3 and β1 integrin combination also presented potential advantages regarding safety compared to direct HER2 targeting.
Conclusions:
- HER3 is validated as a central mediator of HER2's tumorigenic functions.
- Targeting HER3 in combination with β1 integrin inhibitors represents a promising therapeutic strategy for HER2-amplified breast cancers.
- HER3 is identified as a valuable target for developing novel lateral combination therapies.
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