Trastuzumab Has Preferential Activity against Breast Cancers Driven by HER2 Homodimers

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 non-transformed 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. As expected, 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, 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 HER2-overexpressing patients. Together, our findings corroborate the hypothesis that HER2 oligomeric states regulate HER2 signaling, also arguing that trastuzumab sensitivity of homodimers reflects an inability to activate the PI3K/AKT pathway. One of the most important clinical implications of our results is that high levels of HER2 homodimers may predict a positive response to trastuzumab.

Antiproliferative Effect of Lapatinib in HER2-Positive and HER2-Negative/HER3-High Breast Cancer: Results of the Presurgical Randomized MAPLE Trial (CRUK E/06/039)

“…21). In contrast with the antibody trastuzumab that recognizes an epitope on the extracellular domain that is only exposed in the case of HER2 homodimers (21,22), the TKI lapatinib inhibits the intracellular domains of EGFR and HER2, and as such may also target various HER2-containing heterodimers. HER3 has a docking site for the p85 subunit of PI3K and acts as the preferred heterodimerization partner for HER2.…”

Targeting focal adhesion kinase in ER+/HER2+ breast cancer improves trastuzumab response

“…However, there is also the possibility that HER2 heterodimerisation patterns in these cells might be different from those in trastuzumabsensitive BT-474 cells; this in turn might provide differential inputs into Akt regulation in these cell models, a hypothesis supported by Ghosh et al (2011), who demonstrated that HER2 heterodimerisation can be associated with a lower response to trastuzumab. Alternatively, the residual Akt signalling (which is still substantial) observed in MDA-361 cells even after trastuzumab treatment may be enough to maintain cell proliferation, as is the case for PF878 monotherapy.…”

Preexisting oncogenic events impact trastuzumab sensitivity in ERBB2-amplified gastroesophageal adenocarcinoma

“…Further studies have investigated the impact on trastuzumab sensitivity of other ERBB members in breast cancer. For example, trastuzumab reportedly had the greatest benefit for ERBB2-amplified breast cancer driven by ERBB2:ERBB2 homodimers (19). Moreover, ERBB3:ERBB2 dimerization has been reported in many ERBB2-amplified breast cancers (20), leading to investigation of the addition of ERBB3 inhibitors to ERBB2-directed therapy (21)(22)(23)(24).…”