title: The anti-cancer activity of the mTORC1/2 dual inhibitor XL388 in preclinical osteosarcoma models.
abstract: 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.
authors.affiliation: Department of Orthopedics, The Affiliated Jiangyin Hospital of Medical College of Southeast University, Jiangyin City, 215600, China.
authors.forename: Yun-Rong
authors.initials: YR
authors.lastname: Zhu
authors.affiliation: The Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou 215000, China.
authors.forename: Xiao-Zhong
authors.initials: XZ
authors.lastname: Zhou
authors.affiliation: The Center of Diagnosis and Treatment for Children's Bone Diseases, The Children's Hospital Affiliated to Soochow University, Suzhou, Jiangsu, 215000, China.
authors.forename: Lun-Qing
authors.initials: LQ
authors.lastname: Zhu
authors.affiliation: Joint group of Orthopedic Department, Affiliated Hospital of Nanjing University of TCM, Nanjing 210029, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Yao
authors.affiliation: Department of Orthopedics, The Affiliated Jiangyin Hospital of Medical College of Southeast University, Jiangyin City, 215600, China.
authors.forename: Jian-Feng
authors.initials: JF
authors.lastname: Fang
authors.affiliation: Department of Orthopedics, The Affiliated Jiangyin Hospital of Medical College of Southeast University, Jiangyin City, 215600, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhou
authors.affiliation: Department of Orthopedics, The Affiliated Jiangyin Hospital of Medical College of Southeast University, Jiangyin City, 215600, China.
authors.forename: Xiong-Wei
authors.initials: XW
authors.lastname: Deng
authors.affiliation: Department of Orthopedics, The Affiliated Jiangyin Hospital of Medical College of Southeast University, Jiangyin City, 215600, China.
authors.forename: Yun-Qing
authors.initials: YQ
authors.lastname: Zhang
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000293:Adolescent; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy; D000071186:Beclin-1 / Q000378:metabolism; D001859:Bone Neoplasms / Q000188:drug therapy*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D020868:Gene Silencing; D006801:Humans; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism*; D000076225:Mechanistic Target of Rapamycin Complex 2 / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D012516:Osteosarcoma / Q000188:drug therapy* / Q000378:metabolism; D010766:Phosphorylation; D013450:Sulfones / Q000494:pharmacology*; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D000071186:Beclin-1; D013450:Sulfones; C000626295:XL388; C025946:3-methyladenine; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D020169:Caspases; D000225:Adenine
keywords: AKT; XL388; autophagy and chemo-sensitization; mTORC1/2; osteosarcoma (OS)