HDAC6 Inhibitor Strengthens The Anti-proliferative Activity Of PI3K/mTOR Inhibitor BEZ235 Bysuppressing Up-regulation Of RTKs In Breast Cancer

NVP-BEZ235,an available dual PI3K/mTOR inhibitor,showed anti-tumor effect and provided a therapy strategy in carcinomas.However,BEZ235 treatment caused up-regulation of multiple upstream RTKs,which may impair the efficacy of NVP-BEZ235.HDAC6,a class Ⅱ histone deacetylase,is associated with multiple RTKs,including EGFR,HER2,PDGFR and VEFGR.The aim of this study was to detect whether co-treatment with TST,a HDAC6 inhibitor,in breast cancer cells,would enhance the anti-cancer effects of NVP-BEZ235.In this study,we described that treatment of breast cancer cell lines T47D and BT474 with BEZ235 induced inactivation of PI3K/mTOR signaling transitorily accompanied with increased expression of multiple upstream RTKs,including ERBB family,IGF-1 receptor,Insulin receptor and so on.TST destabilized these tested tyrosine kinases,abrogated AKT reactivation and promoted the anti-proliferative activity of BEZ235 in these breast cancer cells.Co-treatment with BEZ235 and TST also displayed synergistic effect on DNA synthesis and arrest of cell cycle.In conclusion,the co-treatment with PI3K/mTOR inhibitor BEZ235 and HDAC6 inhibitor TST displayed synergistic activity against proliferation of T47D and BT474 cells and established a rationable combination therapy to treat breast cancer.