Preclinical Development of novel therapeutic approaches in models resistant to targeted therapies in HER2-positive mammary breast cancer

HER2 enriched mammary breast cancer represents 15-25% of mammary carcinomas and is associated to increased aggressiveness and worse prognosis. Advent of targeted therapies against HER2 has improved 5-year survival up to 75%, nevertheless receptor discordance, which is observed in 10.8% of metastasis, as well as resistance to targeted therapies render it a still challenging disease. On the one hand, taking advange of a recently estabilished murine model of spontaneous loss of HER2 expression, we sought to understand the underlying mechanism, to evaluate role of trastuzumab and to identify identify druggable targets in HER2-negative metastasis or relapses of HER2-positive tumors. The study of transcriptome of cell lines with different HER2 expression has permitted us to identify pathways related to the modulation of this more malignant phenotype, which appeared to be promoted by trastuzumab. Some indications emerged for inhibition of PDGFR-B by sunitinib in tumours which have lost HER2 expression. On the other hand, a recently established collection of patient derived xenografts (PDX) was used to obtain models of progression where to evaluate the effect of neratinib, a pan-HER tyrosine kinase inhibitor. No abrupt loss of HER2 expression was registered in these models. Collectively, our data, obtained in ER-/PR- HER2+ PDX, strongly indicate a great and long-lasting efficacy of neratinib even in trastuzumab-resistance and after progression and call for further evaluation of neratinib in advanced clinical settings. In our PDX diagnosed as luminal B expressing HER2 (score 2+), neratinib alone had no effect but synergized with tamoxifen and their combination tended to confer a little survival benefit in vivo, thus underscoring the possible relevance of dual blockade in tumors expressing both hormone receptors and HER2.