Anti-myeloma activity of Akt inhibition is linked to the activation status of PI3K/Akt and MEK/ERK pathway

PLoS One. 2012;7(11):e50005. doi: 10.1371/journal.pone.0050005. Epub 2012 Nov 21.

Abstract

The PI3K/Akt/mTOR signal transduction pathway plays a central role in multiple myeloma (MM) disease progression and development of therapeutic resistance. mTORC1 inhibitors have shown limited efficacy in the clinic, largely attributed to the reactivation of Akt due to rapamycin induced mTORC2 activity. Here, we present promising anti-myeloma activity of MK-2206, a novel allosteric pan-Akt inhibitor, in MM cell lines and patient cells. MK-2206 was able to induce cytotoxicity and inhibit proliferation in all MM cell lines tested, albeit with significant heterogeneity that was highly dependent on basal pAkt levels. MK-2206 was able to inhibit proliferation of MM cells even when cultured with marrow stromal cells or tumor promoting cytokines. The induction of cytotoxicity was due to apoptosis, which at least partially was mediated by caspases. MK-2206 inhibited pAkt and its down-stream targets and up-regulated pErk in MM cells. Using MK-2206 in combination with rapamycin (mTORC1 inhibitor), LY294002 (PI3K inhibitor), or U0126 (MEK1/2 inhibitor), we show that Erk- mediated downstream activation of PI3K/Akt pathway results in resistance to Akt inhibition. These provide the basis for clinical evaluation of MK-2206 alone or in combination in MM and potential use of baseline pAkt and pErk as biomarkers for patient selection.

Publication types

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

MeSH terms

  • Apoptosis / drug effects
  • Butadienes / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Chromones / pharmacology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Heterocyclic Compounds, 3-Ring / pharmacology*
  • Humans
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / genetics
  • Mechanistic Target of Rapamycin Complex 1
  • Morpholines / pharmacology
  • Multiple Myeloma* / genetics
  • Multiple Myeloma* / metabolism
  • Multiprotein Complexes / antagonists & inhibitors
  • Multiprotein Complexes / metabolism
  • Nitriles / pharmacology
  • Phosphatidylinositol 3-Kinases* / genetics
  • Phosphatidylinositol 3-Kinases* / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt* / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt* / metabolism
  • Signal Transduction / drug effects
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism
  • Transcriptional Activation / drug effects
  • Transcriptional Activation / genetics

Substances

  • Butadienes
  • Chromones
  • Heterocyclic Compounds, 3-Ring
  • MK 2206
  • Morpholines
  • Multiprotein Complexes
  • Nitriles
  • Phosphoinositide-3 Kinase Inhibitors
  • U 0126
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Proto-Oncogene Proteins c-akt
  • Sirolimus