The anti-cancer activity of the mTORC1/2 dual inhibitor XL388 in preclinical osteosarcoma models
- Oncotarget. 2016 Aug 2;7(31):49527-49538. doi: 10.18632/oncotarget.10389.
- 1. Department of Orthopedics, The Affiliated Jiangyin Hospital of Medical College of Southeast University, Jiangyin City, 215600, China.
- 2. The Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou 215000, China.
- 3. The Center of Diagnosis and Treatment for Children's Bone Diseases, The Children's Hospital Affiliated to Soochow University, Suzhou, Jiangsu, 215000, China.
- 4. Joint group of Orthopedic Department, Affiliated Hospital of Nanjing University of TCM, Nanjing 210029, China.
In the present study, we investigated the activity of XL388, a novel mammalian target of rapamycin (mTOR) complex 1/2 (mTORC1/2) dual inhibitor, in preclinical osteosarcoma (OS) models. XL388 was cytotoxic, cytostatic and pro-apoptotic to multiple established OS cell lines and primary human OS cells. XL388 blocked mTORC1/2 activation and downregulated cyclin D1/B1 expressions in OS cells, leaving Akt Thr-308 phosphorylation un-affected. Intriguingly, Akt1 T308A mutation potentiated XL388-induced cytotoxicity in OS cells. XL388 activated cytoprotective Autophagy in OS cells. Autophagy inhibition, either pharmacologically or genetically, augmented XL388-induced anti-OS activity. Further, XL388 oral administration inhibited U2OS xenografts growth in severe combined immuno-deficient (SCID) mice. Such activity was enhanced with co-administration of the Autophagy inhibitor 3-methyladenine (3-MA). Similarly, Beclin-1-silenced U2OS xenografts were remarkably more sensitive to XL388. Thus, concurrent blockage of mTORC1/2 with XL388 may have therapeutic value for OS.