Dual mTORC1/mTORC2 inhibition diminishes Akt activation and induces Puma-dependent apoptosis in lymphoid malignancies

Blood. 2012 Jan 12;119(2):476-87. doi: 10.1182/blood-2011-04-346601. Epub 2011 Nov 11.

Abstract

The mammalian target of rapamycin (mTOR) plays crucial roles in proliferative and antiapoptotic signaling in lymphoid malignancies. Rapamycin analogs, which are allosteric mTOR complex 1 (mTORC1) inhibitors, are active in mantle cell lymphoma and other lymphoid neoplasms, but responses are usually partial and short-lived. In the present study we compared the effects of rapamycin with the dual mTORC1/mTORC2 inhibitor OSI-027 in cell lines and clinical samples representing divers lymphoid malignancies. In contrast to rapamycin, OSI-027 markedly diminished proliferation and induced apoptosis in a variety of lymphoid cell lines and clinical samples, including specimens of B-cell acute lymphocytic leukemia (ALL), mantle cell lymphoma, marginal zone lymphoma and Sezary syndrome. Additional analysis demonstrated that OSI-027-induced apoptosis depended on transcriptional activation of the PUMA and BIM genes. Overexpression of Bcl-2, which neutralizes Puma and Bim, or loss of procaspase 9 diminished OSI-027-induced apoptosis in vitro. Moreover, OSI-027 inhibited phosphorylation of mTORC1 and mTORC2 substrates, up-regulated Puma, and induced regressions in Jeko xenografts. Collectively, these results not only identify a pathway that is critical for the cytotoxicity of dual mTORC1/mTORC2 inhibitors, but also suggest that simultaneously targeting mTORC1 and mTORC2 might be an effective anti-lymphoma strategy in vivo.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins / antagonists & inhibitors*
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • Blotting, Western
  • Cell Proliferation / drug effects
  • Humans
  • Imidazoles / pharmacology*
  • Immunoprecipitation
  • Immunosuppressive Agents / pharmacology
  • Lymphoma / drug therapy
  • Lymphoma / metabolism
  • Lymphoma / pathology*
  • Mechanistic Target of Rapamycin Complex 1
  • Multiprotein Complexes
  • Phosphorylation / drug effects
  • Proteins / antagonists & inhibitors*
  • Proteins / genetics
  • Proteins / metabolism
  • Proto-Oncogene Proteins / antagonists & inhibitors*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism*
  • RNA, Messenger / genetics
  • RNA, Small Interfering / genetics
  • Real-Time Polymerase Chain Reaction
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Triazines / pharmacology*
  • Tumor Cells, Cultured

Substances

  • Apoptosis Regulatory Proteins
  • BBC3 protein, human
  • CRTC2 protein, human
  • Imidazoles
  • Immunosuppressive Agents
  • Multiprotein Complexes
  • OSI 027
  • Proteins
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • RNA, Small Interfering
  • Transcription Factors
  • Triazines
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Proto-Oncogene Proteins c-akt
  • Sirolimus