Anti-Myeloma Activity of Akt Inhibition Is Linked to the Activation Status of PI3K/Akt and MEK/ERK Pathway

Vijay Ramakrishnan, Teresa Kimlinger, Jessica Haug, Utkarsh Painuly, Linda Wellik, Timothy Halling, S Vincent Rajkumar, Shaji K Kumar

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article numbere50005
JournalPLoS One
Volume7
Issue number11
DOIs
StatePublished - Nov 21 2012

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myeloma
MAP Kinase Signaling System
Mitogen-Activated Protein Kinase Kinases
phosphatidylinositol 3-kinase
Multiple Myeloma
Phosphatidylinositol 3-Kinases
Chemical activation
Sirolimus
Cytotoxicity
cytotoxicity
Cells
Cell Line
cell lines
Signal transduction
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Biomarkers
Stromal Cells
Caspases
stromal cells
caspases

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Anti-Myeloma Activity of Akt Inhibition Is Linked to the Activation Status of PI3K/Akt and MEK/ERK Pathway. / Ramakrishnan, Vijay; Kimlinger, Teresa; Haug, Jessica; Painuly, Utkarsh; Wellik, Linda; Halling, Timothy; Rajkumar, S Vincent; Kumar, Shaji K.

In: PLoS One, Vol. 7, No. 11, e50005, 21.11.2012.

Research output: Contribution to journalArticle

Ramakrishnan, Vijay ; Kimlinger, Teresa ; Haug, Jessica ; Painuly, Utkarsh ; Wellik, Linda ; Halling, Timothy ; Rajkumar, S Vincent ; Kumar, Shaji K. / Anti-Myeloma Activity of Akt Inhibition Is Linked to the Activation Status of PI3K/Akt and MEK/ERK Pathway. In: PLoS One. 2012 ; Vol. 7, No. 11.
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