A Kinase Inhibitor Targeted to mTORC1 Drives Regression in Glioblastoma

• Published in: Cancer cell 2017-03, Vol.31 (3), p.424-435
• Main Authors: Fan, QiWen, Aksoy, Ozlem, Wong, Robyn A., Ilkhanizadeh, Shirin, Novotny, Chris J., Gustafson, William C., Truong, Albert Yi-Que, Cayanan, Geraldine, Simonds, Erin F., Haas-Kogan, Daphne, Phillips, Joanna J., Nicolaides, Theodore, Okaniwa, Masanori, Shokat, Kevan M., Weiss, William A.
• Format: Article
• Language: English
• Subjects: Animals; Brain Neoplasms - drug therapy; Cell Line, Tumor; Female; FKBP12, FK506 binding protein 12; FRB, FK506 rapamycin binding; GBM, glioblastoma; Glioblastoma - drug therapy; Humans; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Inbred BALB C; mTOR mechanistic target of rapamycin; mTORC1, mTOR complex 1; mTORC2, mTOR complex 2; Multiprotein Complexes - antagonists & inhibitors; PI3K, phosphatidylinositol 3' kinase; Protein Kinase Inhibitors - therapeutic use; Sirolimus - therapeutic use; Tacrolimus Binding Protein 1A - physiology; TOR Serine-Threonine Kinases - antagonists & inhibitors; TORKi, mTOR kinase inhibitor
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2017.01.014

Although signaling from phosphatidylinositol 3-kinase (PI3K) and AKT to mechanistic target of rapamycin (mTOR) is prominently dysregulated in high-grade glial brain tumors, blockade of PI3K or AKT minimally affects downstream mTOR activity in glioma. Allosteric mTOR inhibitors, such as rapamycin, incompletely block mTORC1 compared with mTOR kinase inhibitors (TORKi). Here, we compared RapaLink-1, a TORKi linked to rapamycin, with earlier-generation mTOR inhibitors. Compared with rapamycin and Rapalink-1, TORKi showed poor durability. RapaLink-1 associated with FKBP12, an abundant mTOR-interacting protein, enabling accumulation of RapaLink-1. RapaLink-1 showed better efficacy than rapamycin or TORKi, potently blocking cancer-derived, activating mutants of mTOR. Our study re-establishes mTOR as a central target in glioma and traces the failure of existing drugs to incomplete/nondurable inhibition of mTORC1. •The TORKi MLN0128 shows poor residence time, underlying poor in vivo efficacy•RapaLink-1 shows improved potency compared with rapamycin and MLN0128•RapaLink-1 binding to FKBP12 results in targeted and durable inhibition of mTORC1•RapaLink-1 crosses the blood-brain barrier, blocking three brain cancer models in vivo Fan et al. target mTORC1 activity in glioblastoma (GBM) with RapaLink-1, which is comprised of rapamycin linked to an mTOR kinase inhibitor. RapaLink-1 decreases mTORC1 activity in the brain and suppresses the growth of GBM xenografts and a genetically engineered mouse model of brain cancer in vivo.