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.
Highlights
Multiple myeloma (MM) is an incurable plasma cell neoplasm that has seen considerable improvement in patient survival in the last decade due to the introduction of several effective therapies [1]
A critical down-stream member of the PI3K/Akt pathway is the mammalian target of rapamycin complex I which is activated by Akt either directly by relieving the PRAS40 mediated inhibition of mTORC1 or indirectly through the inhibition of TSC2 [14,15]
Given the importance of IGF-1 in myeloma biology, we examined the effect of MK-2206 on inhibiting PI3K/Akt/mTOR pathway in the presence of IGF
Summary
Multiple myeloma (MM) is an incurable plasma cell neoplasm that has seen considerable improvement in patient survival in the last decade due to the introduction of several effective therapies [1]. The PI3Ks phosphorylate phosphotidylinositol-4,5-bisphosphate (PIP2) to PIP3. PIP3 binds to the PH domain of Akt, which causes a conformational change in Akt exposing amino acids (Thr308 and Ser473) that are phosphorylated and activated [4,5]. Akt phosphorylates and modulates multiple proteins leading to increased cell growth and survival, decreased apoptosis and drug resistance [6,7,8,9,10,11,12,13]. MTORC1 regulates cell growth, metabolism, translation and autophagy [16,17]
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