Abstract A10: Upregulation of ADAM17 protease and HER ligands through a PKB negative feedback loop mediates acquired resistance to Trastuzumab in HER2 overexpressed breast cancer

Abstract

Abstract The decision to treat breast cancer patients with Trastuzumab is based on HER2 receptor over-expression or gene amplification. However, even in this selective group of patients, the response rate remains poor and unpredictable. Furthermore, all responders eventually become resistant if Trastuzumab is given as monotherapy. It is still poorly understood how Trastuzumab exerts its mechanism of action and how the acquired resistance to this drug occurs. We have found the molecular mechanisms whereby Trastuzumab fails to abolish HER2 phosphorylation despite being an anti-HER2 monoclonal antibody and have resolved the inconsistencies in the literature regarding the effect of Trastuzumab on HER2 phosphorylation. Trastuzumab did not decrease HER2 phosphorylation in these cells despite the effect on HER2 receptor downregulation. HER2 phosphorylation was maintained by activation of EGFR, HER3 and HER4 via their dimerisation with HER2. The activation of EGFR, HER3 and HER4 was due to an upregulation of HER ligands including heregulin and betacellulin. The upregulation of HER ligands was mediated by ADAM17 through a PKB negative feedback loop. The feedback loop was activated because of the inhibition of PKB by Trastuzumab treatment since upregulation of HER ligands and ADAM17 also occurred when PKB phosphorylation was inhibited by a PKB inhibitor (Akt inhibitor VIII, Akti-1/2). However, the combination treatment of Trastuzumab with a panHER inhibitor JNJ-26483327 was able to abrogate the feedback loop and it was synergistic in tumour inhibition in a BT474 xenograft model. Our data provides evidence that Trastuzumab resistance can be mediated by activation of HER family ligands as a direct consequence of inhibition of HER2 and PKB signalling. This offers treatment opportunities for overcoming resistance in these patients, including approaches to target all HER receptors in combination with Trastuzumab treatment. Future research should utilize a systems biology approach to identify other feedback loops that may be involved in the acquired resistance to Trastuzumab treatment in HER2 positive breast cancer. Citation Information: Clin Cancer Res 2010;16(7 Suppl):A10