Abstract
BackgroundThe response rate to EGFR tyrosine kinase inhibitors (TKIs) may be poor and unpredictable in cancer patients with EGFR expression itself being an inadequate response indicator. There is limited understanding of the mechanisms underlying this resistance. Furthermore, although TKIs suppress the growth of HER2-overexpressing breast tumor cells, they do not fully inhibit HER2 oncogenic function at physiological doses.Methodology and Principal FindingsHere we have provided a molecular mechanism of how HER2 oncogenic function escapes TKIs' inhibition via alternative HER receptor activation as a result of autocrine ligand release. Using both Förster Resonance Energy Transfer (FRET) which monitors in situ HER receptor phosphorylation as well as classical biochemical analysis, we have shown that the specific tyrosine kinase inhibitors (TKIs) of EGFR, AG1478 and Iressa (Gefitinib) decreased EGFR and HER3 phosphorylation through the inhibition of EGFR/HER3 dimerization. Consequent to this, we demonstrate that cleavage of HER4 and dimerization of HER4/HER2 occur together with reactivation of HER3 via HER2/HER3, leading to persistent HER2 phosphorylation in the now resistant, surviving cells. These drug treatment–induced processes were found to be mediated by the release of ligands including heregulin and betacellulin that activate HER3 and HER4 via HER2. Whereas an anti-betacellulin antibody in combination with Iressa increased the anti-proliferative effect in resistant cells, ligands such as heregulin and betacellulin rendered sensitive SKBR3 cells resistant to Iressa.Conclusions and SignificanceThese results demonstrate the role of drug-induced autocrine events leading to the activation of alternative HER receptors in maintaining HER2 phosphorylation and in mediating resistance to EGFR tyrosine kinase inhibitors (TKIs) in breast cancer cells, and hence specify treatment opportunities to overcome resistance in patients.
Highlights
The human Epidermal Growth Factor Receptor (HER, known as ErbB) family consists of four receptors EGFR (HER1 or ErbB-1), HER2 (ErbB-2), HER3 (ErbB-3) and HER4 (ErbB-4) binding more than 10 polypeptide ligands between them [1]
These results demonstrate the role of drug-induced autocrine events leading to the activation of alternative HER receptors in maintaining HER2 phosphorylation and in mediating resistance to EGFR tyrosine kinase inhibitors (TKIs) in breast cancer cells, and specify treatment opportunities to overcome resistance in patients
We applied Forster Resonance Energy Transfer (FRET) to study the effect of TKIs on HER2 phosphorylation since FRET can detect variations between single cells not accessible through other biochemical methods
Summary
The human Epidermal Growth Factor Receptor (HER, known as ErbB) family consists of four receptors EGFR (HER1 or ErbB-1), HER2 (ErbB-2), HER3 (ErbB-3) and HER4 (ErbB-4) binding more than 10 polypeptide ligands between them [1]. The HER receptors play a crucial role in breast cancer and many other types of cancer [2], generating much interest in understanding their individual and combinatorial actions. These receptors belong to subclass I of the superfamily of Receptor Tyrosine Kinases (RTKs) which are transmembrane receptors with an intrinsic ability to phosphorylate their tyrosine residues in the cytoplasmic domains to transduce signals [3]. For example EGFR tyrosine kinase inhibitor (TKI) like Iressa (Gefitinib, ZD 1839) which targets the EGFR receptor inhibits the PI3K and PKB pathway via HER3 [11]. The response rate to EGFR tyrosine kinase inhibitors (TKIs) may be poor and unpredictable in cancer patients with EGFR expression itself being an inadequate response indicator. TKIs suppress the growth of HER2-overexpressing breast tumor cells, they do not fully inhibit HER2 oncogenic function at physiological doses
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