New strategies to overcome resistance to mammalian target of rapamycin inhibitors in breast cancer

Abstract

To review the studies addressing mammalian target of rapamycin (mTOR) inhibitors in breast cancer and resistance to rapalogs. Preclinical and clinical studies have suggested mTOR inhibitors may help overcome the resistance to endocrine therapy and trastuzumab. Despite much interest, knowledge of the mechanism and molecular response to mTOR inhibitors is incomplete. Resistance to mTOR inhibitors has been explored in preclinical studies and can be defined as primary, associated with amplifications or mutations of different kinases, or secondary, in which rapalog activates the feedback loops involving the insulin-like growth factor I receptor (IGF-IR), platelet-derived growth factor receptor and mitogen-activated protein kinase (MAPK) pathway. Current clinical trials are testing the combinations of rapamycin with other kinase inhibitors including IGF-IR, phosphoinositide 3-kinase and MAPK-extracellular signal-regulated kinase inhibitors. Recent findings on the resistance to rapalogs have stimulated the assessment of combinations of inhibitors in clinical trials. This review summarizes the current knowledge of primary and secondary rapalog resistance, and the current efforts to overcome this resistance.