Targeting downstream effectors of epidermal growth factor receptor/HER2 in breast cancer with either farnesyltransferase inhibitors or mTOR antagonists

Abstract

In breast cancer, there is an increasing recognition of the pivotal role played by the epidermal growth factor receptor (EGFR) and HER2 together with the various downstream signal transduction pathways, in particular the Ras/Raf/Mek/erk1/2 pathway that regulates cell proliferation together with the phosphatidylinositol-3-OH kinase (PI3K)/Akt/mTOR pathway that is implicated in cell survival. While monoclonal antibodies and small molecule tyrosine kinase inhibitors targeted against EGFR/HER2 are now being used for breast cancer therapy, there is considerable interest in also targeting the critical downstream pathways that cells may remain dependent upon. Activation of these downstream pathways in breast cancer may be associated with resistance to either conventional endocrine or cytotoxic therapies or, indeed, lack of response to EGFR/HER2-targeted approaches. Farnesyltransferase inhibitors (FTIs) were initially developed to target Ras activation, although their mechanism of action may be more nonspecific. Trials in breast cancer have been completed with FTIs alone or in combination with endocrine or cytotoxic therapy. Activation of the PI3K/Akt pathway has also been associated with resistance to either tamoxifen or estrogen deprivation, and preclinical studies have shown that the mTOR antagonists can restore endocrine sensitivity in breast cancer cells. Randomized phase II/III trials of aromatase inhibitors combined with mTOR antagonists are in progress and have been powered to detect whether combined therapy can significantly prolong time to disease progression compared to endocrine therapy alone. Finally, preclinical experiments are now investigating whether downstream agents should be combined with upstream EGFR/HER2 therapies to produce maximal blockade of vertical signal transduction pathways. Subsequent trials will be needed to see whether combinations of novel STIs are well tolerated and how they may further enhance clinical benefit in breast cancer.