Modest up-regulation of either HER-
ligands or receptors has been implicated in acquired endocrine resistance.
AZD8931, a dual
tyrosine kinase inhibitor (TKI) of epithelial
growth factor receptor (EGFR)/HER2, has been shown to more effectively block
ligand-dependent HER signaling than the HER TKIs
lapatinib or
gefitinib. We therefore examined the effect of
AZD8931 in ER-positive/HER2-negative
breast cancer cells with acquired resistance to
tamoxifen, where there is
ligand up-regulation associated with HER pathway activation.
RNA-seq
ligand profiling and levels of HER receptors and signaling by western blotting were conducted in ER+ MCF7 and T47D parental cells and their Tam-resistant derivatives (TamRes). In vitro cell growth and apoptosis and HER
ligand-stimulated signaling were measured in response to endocrine and HER TKIs. For studies in vivo, transplantable MCF7/TamRes xenografts were treated with
tamoxifen or
fulvestrant, either alone or in combination with
AZD8931.
AZD8931 only minimally enhanced endocrine sensitivity in MCF7 parental cells, but showed a greater effect in the T47D parental model.
AZD8931 combined with either
tamoxifen or
fulvestrant inhibited cell growth more than
lapatinib in T47D TamRes cells, and was also significantly, though modestly, more potent in MCF7 TamRes cells. In both TamRes models,
AZD8931 significantly inhibited cell proliferation and induced apoptosis. Under
ligand-stimulated conditions,
AZD8931 more potently inhibited HER signaling than
lapatinib or
gefitinib.
AZD8931 also significantly delayed the growth of MCF7 TamRes xenografts in the presence of
tamoxifen or
fulvestrant. The strongest inhibition was achieved with a
fulvestrant and
AZD8931 combination, though no
tumor regression was observed. This study provides evidence that
AZD8931 has greater inhibitory efficacy in
tamoxifen-resistant settings than in an endocrine
therapy naïve setting. The absence of
tumor regression, however, suggests that additional escape pathways contribute to resistant growth and will need to be targeted to fully circumvent
tamoxifen resistance.