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Trastuzumab has preferential activity against breast cancers driven by HER2 homodimers
Ritwik Ghosh1, Archana Narasanna, Shizhen Emily Wang
1Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee 37232, USA.
Abstract:
In breast cancer cells with HER2 gene amplification, HER2 receptors exist on the cell surface as monomers, homodimers, and heterodimers with EGFR/HER3. The therapeutic antibody trastuzumab, an approved therapy for HER2(+) breast cancer, cannot block ligand-induced HER2 heterodimers, suggesting it cannot effectively inhibit HER2 signaling. Hence, HER2 oligomeric states may predict the odds of a clinical response to trastuzumab in HER2-driven tumors. To test this hypothesis, we generated nontransformed human MCF10A mammary epithelial cells stably expressing a chimeric HER2-FKBP molecule that could be conditionally induced to homodimerize by adding the FKBP ligand AP1510, or instead induced to heterodimerize with EGFR or HER3 by adding the heterodimer ligands EGF/TGFα or heregulin. AP1510, EGF, and heregulin each induced growth of MCF10A cells expressing HER2-FKBP. Trastuzumab inhibited homodimer-mediated but not heterodimer-mediated cell growth. In contrast, the HER2 antibody pertuzumab, which blocks HER2 heterodimerization, inhibited growth induced by heregulin but not AP1510. Lastly, the HER2/EGFR tyrosine kinase inhibitor lapatinib blocked both homodimer- and heterodimer-induced growth. AP1510 triggered phosphorylation of Erk1/2 but not AKT, whereas trastuzumab inhibited AP1510-induced Erk1/2 phosphorylation and Shc-HER2 homodimer binding, but not TGFα-induced AKT phosphorylation. Consistent with these observations, high levels of HER2 homodimers correlated with longer time to progression following trastuzumab therapy in a cohort of patients with HER2-overexpressing breast cancer. Together, our findings confirm the notion that HER2 oligomeric states regulate HER2 signaling, also arguing that trastuzumab sensitivity of homodimers may reflect their inability to activate the PI3K (phosphoinositide 3-kinase)/AKT pathway. A clinical implication of our results is that high levels of HER2 homodimers may predict a positive response to trastuzumab.
Insights
HER2 receptor dimerization state impacts breast cancer treatment. HER2 homodimers may predict response to trastuzumab therapy, unlike heterodimers. This finding could guide personalized HER2-positive breast cancer treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- HER2 amplification drives breast cancer, with HER2 receptors existing as monomers, homodimers, and heterodimers.
- Trastuzumab, a HER2-targeted therapy, struggles to inhibit ligand-induced HER2 heterodimers, limiting its efficacy.
- HER2 oligomeric states may predict clinical response to trastuzumab in HER2-driven tumors.
Purpose of the Study:
- To investigate the role of HER2 receptor oligomeric states in HER2 signaling and response to HER2-targeted therapies.
- To determine if HER2 homodimerization or heterodimerization influences sensitivity to trastuzumab, pertuzumab, and lapatinib.
- To correlate HER2 homodimer levels with clinical outcomes in patients with HER2-overexpressing breast cancer.
Main Methods:
- Generated MCF10A cells expressing a chimeric HER2-FKBP molecule for inducible homodimerization or heterodimerization with EGFR/HER3.
- Administered AP1510 (homodimerizer), EGF/TGFα, or heregulin (heterodimerizers) to induce specific HER2 oligomeric states.
- Treated cells with trastuzumab, pertuzumab, or lapatinib to assess differential inhibition of growth and signaling pathways (Erk1/2, AKT).
- Analyzed HER2 homodimer binding and phosphorylation events.
- Correlated HER2 homodimer levels with time to progression in a patient cohort.
Main Results:
- AP1510, EGF, and heregulin induced cell growth, with trastuzumab inhibiting only homodimer-mediated growth.
- Pertuzumab inhibited heterodimer-mediated growth (heregulin) but not homodimer-mediated growth (AP1510).
- Lapatinib inhibited growth induced by both homodimers and heterodimers.
- Trastuzumab blocked AP1510-induced Erk1/2 phosphorylation and Shc-HER2 homodimer binding.
- High HER2 homodimer levels correlated with longer time to progression after trastuzumab therapy.
Conclusions:
- HER2 oligomeric states (homodimers vs. heterodimers) differentially regulate HER2 signaling pathways.
- Trastuzumab sensitivity to HER2 homodimers may stem from their inability to activate the PI3K/AKT pathway.
- High levels of HER2 homodimers are a potential predictive biomarker for positive response to trastuzumab in HER2-overexpressing breast cancer.
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