title: Investigational drug MLN0128, a novel TORC1/2 inhibitor, demonstrates potent oral antitumor activity in human breast cancer xenograft models.
abstract: Aberrant activation of the mammalian target of rapamycin (mTOR) signaling plays an important role in breast cancer progression and represents a potential therapeutic target for breast cancer. In this study, we report the impact of the investigational drug MLN0128, a potent and selective small molecule active-site TORC1/2 kinase inhibitor, on tumor growth and metastasis using human breast cancer xenograft models. We assessed in vitro antiproliferative activity of MLN0128 in a panel of breast cancer cell lines. We next evaluated the impact of MLN0128 on tumor growth, angiogenesis and metastasis using mammary fat pad xenograft models of a non-VEGF (ML20) and a VEGF-driven (MV165) MCF-7 sublines harboring PIK3CA mutations. MLN0128 potently inhibited cell proliferation in various breast cancer cell lines harboring PIK3CA (IC(50): 1.5-53 nM), PTEN (IC(50): 1-149 nM), KRAS, and/or BRAF mutations (IC(50): 13-162 nM), and in human endothelial cells (IC(50): 33-40 nM) in vitro. In vivo, MLN0128 decreased primary tumor growth significantly in both non-VEGF (ML20; p = 0.05) and VEGF-driven MCF-7 (MV165; p = 0.014) xenograft models. MLN0128 decreased the phosphorylation of Akt, S6, 4E-BP1, and NDRG1 in both models. In contrast, rapamycin increased Akt activity and failed to reduce the phosphorylation of 4E-BP1, PRAS40, and NDRG1. VEGF-induced lung metastasis in MV165 is inhibited by MLN0128 and rapamycin. In conclusion, MLN0128 inhibits TORC1/2-dependent signaling in preclinical models of breast cancer. MLN0128 appears to be superior in blocking mTORC1/2 signaling in contrast to rapamycin. Our findings support the clinical research of MLN0128 in patients with breast cancer and metastasis.
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Walther Hall, 980 W Walnut Street, Building R3, Room C230, Indianapolis, IN 46202, USA. ypolar@iupui.edu
authors.forename: Yesim
authors.initials: Y
authors.lastname: Gökmen-Polar
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Toroni
authors.forename: Kerry L
authors.initials: KL
authors.lastname: Sanders
authors.forename: Rutika
authors.initials: R
authors.lastname: Mehta
authors.forename: Sunil
authors.initials: S
authors.lastname: Badve
authors.forename: Christian
authors.initials: C
authors.lastname: Rommel
authors.forename: George W
authors.initials: GW
authors.lastname: Sledge
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000494:pharmacology*; D001583:Benzoxazoles / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D058534:Class I Phosphatidylinositol 3-Kinases; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008819:Mice, Nude; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009154:Mutation; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D051059:PTEN Phosphohydrolase / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000097:blood / Q000494:pharmacology*; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D000225:Adenine / Q000031:analogs & derivatives
chemical_list: D000970:Antineoplastic Agents; D001583:Benzoxazoles; D058534:Class I Phosphatidylinositol 3-Kinases; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D011506:Proteins; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D011743:Pyrimidines; D058570:TOR Serine-Threonine Kinases; D042461:Vascular Endothelial Growth Factor A; C484760:PIK3CA protein, human; C482119:BRAF protein, human; C494929:PTEN protein, human; C572449:sapanisertib; D000225:Adenine