Understanding endocrine resistance: the critical need for sequential samples from clinical breast cancer and novel in vitromodels

Excerpt

Although the mechanisms that underlie endocrine resistance in breast cancer are complex, their investigation has potential to reveal new targets to treat or even prevent this undesirable state. Of particular interest are growth factor receptor kinase cascades; there are experimental data implicating increased signalling through these pathways in both de novo and acquired resistance to tamoxifen. Various estrogen receptor (ER)-negative and ER-positive de novo tamoxifen resistant cell models have elevated epidermal growth factor receptor (EGFR)/HER2 signalling. In acquired tamoxifen resistance, models such as TAMR are equally persuasive in implicating EGFR, HER2 and insulin-like growth factor-1 receptor, and activity of extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein kinase (MAPK) and phosphoinositol 3-kinase (PI3K)/AKT [1]. Signal transduction inhibitors (STIs) such as the EGFR selective tyrosine kinase inhibitor gefitinib and agents that target the increased downstream intracellular kinases can be growth inhibitory in both resistance settings. As such, clinical trials are underway with STI monotherapy in recurrent tamoxifen resistant, advanced/metastatic and ER-negative breast cancer. …