7.3.2　Everolimus

Everolimus is a macrolide derivative of rapamycin.The drug was first marketed in Sweden in 2003，when it was mainly used to prevent rejection after kidney transplantation and heart transplant surgery.It acts to inhibit tumors mainly through a key molecule mTOR acting downstream of the PI3KAKT pathway.Everolimus can also inhibit tumor angiogenesis and inhibit anti-tumor effects by inhibiting the production of hypoxia-inducible factor-1（HIF-1）and VEGF in tumor cells and the indirect effect of VEGF-induced endothelial cell proliferation.In October 2007，Europe approved the indication of everolimus for the treatment of gastrointestinal neuroendocrine tumors.In March 2009，the US FDA approved its indication for kidney cancer（trade name Afinitor）.Currently，everolimus is also conducting clinical research in a variety of other tumors，including breast cancer.(https://www.daowen.com)

One possible mechanism of endocrine therapy resistance is the crosstalk between the ER pathway and other growth signaling pathways.Even if the ER pathway is inhibited，abnormal activation of other growth signaling pathways leads to endocrine resistance.Therefore，endocrine therapy combined with growth signaling pathway targeting drugs may reverse endocrine therapy resistance.The PI3K-AKTmTOR pathway is one of the major signaling pathways downstream of many cell membrane surface receptors（EGFR family，VEGFR，PDGFR，IGFR），so inhibition of downstream pathways may overcome targeted therapeutics such as trastuzumab.This theory has been initially confirmed in preclinical and phase Ⅰ～Ⅱ clinical trials.At present，everolimus is conducting two phase Ⅲ clinical randomized trials（BOLERO-1，BOLERO-3）for HER-2 positive breast cancer compared with chemotherapy plus trastuzumab+everolimus.Whether Moss can overcome the resistance of trastuzumab.In addition，there is a cross-talk between the ER pathway and the PI3K-AKT-mTOR pathway，so mTOR inhibitors may reverse the resistance of endocrine therapy.BOLERO-2 study showed that the combination of exemestane and everolimus significantly prolonged PFS in patients with postmenopausal advanced breast cancer who failed treatment with letrozole or anastrozole（7.4 months vs 3.2 months，P＜1*10-16）.