Antitumor activities of ATP-competitive inhibitors of mTOR in colon cancer cells

Benjamin Blaser,Nicolas Demartines,Anne Dormond-Meuwly,Didier Roulin,Laurent Waselle,Marc Dufour,Olivier Dormond

doi:10.1186/1471-2407-12-86

Antitumor activities of ATP-competitive inhibitors of mTOR in colon cancer cells

Benjamin Blaser, Nicolas Demartines + Show 5 more

Open Access

https://doi.org/10.1186/1471-2407-12-86

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Abstract

BackgroundThe mammalian target of rapamycin (mTOR) is frequently activated in colon cancers due to mutations in the phosphatidylinositol 3-kinase (PI3K) pathway. Targeting mTOR with allosteric inhibitors of mTOR such as rapamycin reduces colon cancer progression in several experimental models. Recently, a new class of mTOR inhibitors that act as ATP-competitive inhibitors of mTOR, has been developed. The effectiveness of these drugs in colon cancer cells has however not been fully characterized.MethodsLS174T, SW480 and DLD-1 colon cancer cell lines were treated with PP242 an ATP-competitive inhibitor of mTOR, NVP-BEZ235, a dual PI3K/mTOR inhibitor or rapamycin. Tumor cell growth, proliferation and survival were assessed by MTS assay, 5-bromo-2'-deoxyuridine (BrDU) incorporation or by quantification of DNA fragmentation respectively. In vivo, the anticancer activity of mTOR inhibitors was evaluated on nude mice bearing colon cancer xenografts.ResultsPP242 and NVP-BEZ235 reduced the growth, proliferation and survival of LS174T and DLD-1 colon cancer cells more efficiently than rapamycin. Similarly, PP242 and NVP-BEZ235 also decreased significantly the proliferation and survival of SW480 cells which were resistant to the effects of rapamycin. In vivo, PP242 and NVP-BEZ235 reduced the growth of xenografts generated from LS174T and SW480 cells. Finally, we also observed that the efficacy of ATP-competitive inhibitors of mTOR was enhanced by U0126, a MEK inhibitor.ConclusionsTaken together, these results show that ATP-competitive inhibitors of mTOR are effective in blocking colon cancer cell growth in vitro and in vivo and thus represent a therapeutic option in colon cancer either alone or in combination with MEK inhibitors.

Highlights

The mammalian target of rapamycin is frequently activated in colon cancers due to mutations in the phosphatidylinositol 3-kinase (PI3K) pathway
LS174T (PI3KCA mutation on exon 20), DLD-1 (PI3KCA mutation on exon 9) and SW480 (PI3KCA wild type) colon cancer cells were treated with increasing concentrations of rapamycin, PP242 [19], a specific mammalian target of rapamycin (mTOR) inhibitor, or NVPBEZ235 [20], a dual PI3K/mTOR inhibitor for six hours
Effect of ATP-competitive inhibitors of mTOR compared to rapamycin on colon cancer cell proliferation and survival To evaluate the activity of rapamycin, NVP-BEZ235 and PP242 on tumor cell growth, colon cancer cell lines were treated for 48 hours and cell growth was analyzed by MTS assay

Summary

Introduction

The mammalian target of rapamycin (mTOR) is frequently activated in colon cancers due to mutations in the phosphatidylinositol 3-kinase (PI3K) pathway. A new class of mTOR inhibitors that act as ATP-competitive inhibitors of mTOR, has been developed. The effectiveness of these drugs in colon cancer cells has not been fully characterized. Drugs that block the vascular endothelial growth factor or the epidermal growth factor receptor have shown clinical activities and have been approved for the treatment of CRC [2]. Despite these new treatments, the prognosis of CRC remains poor and new therapeutic strategies still need to be explored. In a subset of cells, prolonged exposure to rapamycin inhibits mTORC2 [9]

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