Investigational drug MLN0128, a novel TORC1/2 inhibitor, demonstrates potent oral antitumor activity in human breast cancer xenograft models

Yesim Gökmen-Polar, Yi Liu, Rachel A. Toroni, Kerry L. Sanders, Rutika Mehta, Sunil Badve, Christian Rommel, George W. Sledge

Research output: Contribution to journalArticle

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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 (IC50: 1.5-53 nM), PTEN (IC50: 1-149 nM), KRAS, and/or BRAF mutations (IC50: 13-162 nM), and in human endothelial cells (IC50: 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.

Original languageEnglish (US)
Pages (from-to)673-682
Number of pages10
JournalBreast Cancer Research and Treatment
Volume136
Issue number3
DOIs
StatePublished - Dec 1 2012

Fingerprint

Investigational Drugs
Heterografts
Human Activities
Breast Neoplasms
Sirolimus
Inhibitory Concentration 50
Vascular Endothelial Growth Factor A
Neoplasm Metastasis
Growth
Phosphorylation
INK128
mechanistic target of rapamycin complex 1
S 6
Cell Line
Neoplasms
Mutation
Adipose Tissue
Catalytic Domain
Breast
Phosphotransferases

Keywords

  • Breast cancer
  • mTOR
  • PIK3CA
  • TORC1/2 inhibitor
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Investigational drug MLN0128, a novel TORC1/2 inhibitor, demonstrates potent oral antitumor activity in human breast cancer xenograft models. / Gökmen-Polar, Yesim; Liu, Yi; Toroni, Rachel A.; Sanders, Kerry L.; Mehta, Rutika; Badve, Sunil; Rommel, Christian; Sledge, George W.

In: Breast Cancer Research and Treatment, Vol. 136, No. 3, 01.12.2012, p. 673-682.

Research output: Contribution to journalArticle

Gökmen-Polar, Yesim ; Liu, Yi ; Toroni, Rachel A. ; Sanders, Kerry L. ; Mehta, Rutika ; Badve, Sunil ; Rommel, Christian ; Sledge, George W. / Investigational drug MLN0128, a novel TORC1/2 inhibitor, demonstrates potent oral antitumor activity in human breast cancer xenograft models. In: Breast Cancer Research and Treatment. 2012 ; Vol. 136, No. 3. pp. 673-682.
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AB - 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 (IC50: 1.5-53 nM), PTEN (IC50: 1-149 nM), KRAS, and/or BRAF mutations (IC50: 13-162 nM), and in human endothelial cells (IC50: 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.

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