title: Anti-myeloma activity of Akt inhibition is linked to the activation status of PI3K/Akt and MEK/ERK pathway.
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.
authors.affiliation: The Divisions of Hematology, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Vijay
authors.initials: V
authors.lastname: Ramakrishnan
authors.forename: Teresa
authors.initials: T
authors.lastname: Kimlinger
authors.forename: Jessica
authors.initials: J
authors.lastname: Haug
authors.forename: Utkarsh
authors.initials: U
authors.lastname: Painuly
authors.forename: Linda
authors.initials: L
authors.lastname: Wellik
authors.forename: Timothy
authors.initials: T
authors.lastname: Halling
authors.forename: S Vincent
authors.initials: SV
authors.lastname: Rajkumar
authors.forename: Shaji
authors.initials: S
authors.lastname: Kumar
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002867:Chromones / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D000076222:Mechanistic Target of Rapamycin Complex 1; D009025:Morpholines / Q000494:pharmacology; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics
chemical_list: D002070:Butadienes; D002867:Chromones; D006575:Heterocyclic Compounds, 3-Ring; D000076222:Mechanistic Target of Rapamycin Complex 1; D009025:Morpholines; D046912:Multiprotein Complexes; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C548887:MK 2206; C113580:U 0126; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one