posters International Association for Breast Cancer Research 2014

Exploring the HER3 tyrosine kinase as a therapeutic target for treatment of brain metastases (#98)

Jodi M Saunus 1 , Majid Momeny 1 , Leonard Da Silva 1 , Lynne Reid 1 , Flavia Marturana 1 , Jane D Holland 2 , Walter Birchmeier 2 , Parmjit Jat 3 , Sebastian Brandner 3 , Fares Al-Ejeh 4 , Kum Kum Khanna 4 , Georgia Chenevix-Trench 4 , Peter T Simpson 5 , Sunil R Lakhani 1 6 7
  1. XXX UQ Centre for Clinical Research, University of Queensland, Herston 4029, Qld, AUSTRALIA
  2. Department of Cancer Research, Max Delbrueck Center for Molecular Medicine, Berlin, Germany
  3. Div of Neuropathology & Dept of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom
  4. QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
  5. XXX UQ Centre for Clinical Research, University of Queensland, Herston 4029, Qld, AUSTRALIA
  6. University of Queensland School of Medicine, The University of Queensland, Herston, Queensland, Australia
  7. XXX Pathology Queensland, The Royal Brisbane and Women's Hospital, Herston, Queensland, Australia

Development of brain metastases (BM) is associated with neurological decline, morbidity and virtually 100% mortality. BM develop in 10-16% breast cancer patients, with highest incidence for HER2-positive and triple-negative disease. Median survival is 5-22 months depending on treatment and prognostic indicators. There are no standard targeted drug therapies indicated for treatment of BM.

The HER3 (ERBB3) tyrosine kinase is induced in BM compared to matching primary breast and lung cancers, suggesting it could be activated to exploit the abundance of neuregulin (NRG) ligand in the brain. In support of this, we detected very low expression of NRG in clinical samples by RNAseq, and could suppress growth of intracranial MDA-MB-231 breast cancer xenografts by co-grafting a neutralizing Nrg-1 antibody, or treating the mice with Herceptin (i.p.). ERBB3 RNA levels correlate strongly with ERBB2 in clinical samples, but at the protein level HER3 is ubiquitously activated (phosphorylated) in cases comprising a range of HER2 activation levels. IHC analysis of a large archival BM cohort (n=170; 7 primary cancer types) showed strong, complete pHER3 membrane staining in 57.7% cases. Collectively these data suggest that targeting HER3 could be a good therapeutic strategy.

In vitro, we found that Nrg-1 induced phosphorylation cascades involving HER2, HER3, Akt and ERK 1/2 (but not HER4), and increased proliferative and migratory behavior in HER2/3+ breast cancer cell lines. We also tested whether HER3 signaling could promote extracellular protease activity, since protease-mediated modification of the tumour microenvironment is thought to be involved in permeabilising the blood-brain-barrier. Nrg-1 treatment increased expression and activities of Cathepsin B, MMP-2 and MMP-9 in HER2/3+ breast cancer cell lines, and permeabilised a tight human brain microvascular endothelial cell layer in vitro. Treatment with GM6001 (broad spectrum MMP inhibitor), Herceptin or the humanized HER3 monoclonal antibody EV20 opposed Nrg-1-mediated permeability in this assay.