title: MLN0128, an ATP-competitive mTOR kinase inhibitor with potent in vitro and in vivo antitumor activity, as potential therapy for bone and soft-tissue sarcoma.
abstract: The mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that exists in two complexes (mTORC1 and mTORC2) and integrates extracellular and intracellular signals to act as a master regulator of cell growth, survival, and metabolism. The PI3K/AKT/mTOR prosurvival pathway is often dysregulated in multiple sarcoma subtypes. First-generation allosteric inhibitors of mTORC1 (rapalogues) have been extensively tested with great preclinical promise, but have had limited clinical utility. Here, we report that MLN0128, a second-generation, ATP-competitive, pan-mTOR kinase inhibitor, acts on both mTORC1 and mTORC2 and has potent in vitro and in vivo antitumor activity in multiple sarcoma subtypes. In vitro, MLN0128 inhibits mTORC1/2 targets in a concentration-dependent fashion and shows striking antiproliferative effect in rhabdomyosarcoma (RMS), Ewing sarcoma, malignant peripheral nerve sheath tumor, synovial sarcoma, osteosarcoma, and liposarcoma. Unlike rapamycin, MLN0128 inhibits phosphorylation of 4EBP1 and NDRG1 as well as prevents the reactivation of pAKT that occurs via negative feedback release with mTORC1 inhibition alone. In xenograft models, MLN0128 treatment results in suppression of tumor growth with two dosing schedules (1 mg/kg daily and 3 mg/kg b.i.d. t.i.w.). At the 3 mg/kg dosing schedule, MLN0128 treatment results in significantly better tumor growth suppression than rapamycin in RMS and Ewing sarcoma models. In addition, MLN0128 induces apoptosis in models of RMS both in vitro and in vivo. Results from our study strongly suggest that MLN0128 treatment should be explored further as potential therapy for sarcoma.
authors.affiliation: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Emily K
authors.initials: EK
authors.lastname: Slotkin
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York. ppp2115@columbia.edu.
authors.forename: Parag P
authors.initials: PP
authors.lastname: Patwardhan
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Shyamprasad D
authors.initials: SD
authors.lastname: Vasudeva
authors.affiliation: Department of Molecular Pharmacology and Chemistry, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Elisa
authors.initials: E
authors.lastname: de Stanchina
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: William D
authors.initials: WD
authors.lastname: Tap
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York.
authors.forename: Gary K
authors.initials: GK
authors.lastname: Schwartz
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001583:Benzoxazoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D008819:Mice, Nude; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012516:Osteosarcoma / Q000188:drug therapy*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D012509:Sarcoma / Q000188:drug therapy*; D020123:Sirolimus / Q000494:pharmacology; D013379:Substrate Specificity / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000225:Adenine / Q000031:analogs & derivatives
chemical_list: D000255:Adenosine Triphosphate; D000970:Antineoplastic Agents; D001583:Benzoxazoles; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C572449:sapanisertib; D000225:Adenine