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 Journal Article

   

Authors:	Slotkin, E. K.; Patwardhan, P. P.; Vasudeva, S. D.; de Stanchina, E.; Tap, W. D.; Schwartz, G. K.
Article 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 signi ficantly better tumor growth suppression than rapamycin in RMS and Ewing sarcoma models. In addition, MLN0128 induces apoptosis in models ofRMSboth in vitro and in vivo. Results from our study strongly suggest that MLN0128 treatment should be explored further as potential therapy for sarcoma. ©2014 AACR.
Keywords:	osteosarcoma; protein kinase b; s6 kinase; controlled study; protein phosphorylation; treatment outcome; unclassified drug; human cell; drug tolerability; cancer growth; nonhuman; drug megadose; mouse; animal tissue; cell viability; apoptosis; tumor volume; animal experiment; animal model; in vivo study; caspase 3; antineoplastic activity; drug potency; in vitro study; tumor xenograft; ewing sarcoma; cancer inhibition; membrane protein; immunoblotting; soft tissue sarcoma; initiation factor 4e binding protein 1; down regulation; negative feedback; rhabdomyosarcoma; synovial sarcoma; malignant peripheral nerve sheath tumor; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; serum and glucocorticoid regulated kinase 1; protein c myb; rapamycin; protein cleavage; concentration response; embryonal rhabdomyosarcoma; liposarcoma; antiproliferative activity; mammalian target of rapamycin complex 1; caspase 7; mammalian target of rapamycin complex 2; ndrg1 protein; human; female; priority journal; article; ic50; 3 (2 amino 5 benzoxazolyl) 1 isopropyl 1h pyrazolo[3,4 d]pyrimidin 4 amine
Journal Title:	Molecular Cancer Therapeutics
Volume:	14
Issue:	2
ISSN:	1535-7163
Publisher:	American Association for Cancer Research
Date Published:	2015-02-01
Start Page:	395
End Page:	406
Language:	English
DOI:	10.1158/1535-7163.mct-14-0711
PROVIDER:	scopus
PMCID:	PMC4332837
PUBMED:	25519700
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84923698354&partnerID=40&md5=ab5016b84916a01785e3d98cf1d4fc4c
Notes:	Export Date: 2 April 2015 -- Source: Scopus

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