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.

Phosphoinositide Protein Kinase PDPK1 Is a Crucial Cell Signaling Mediator in Multiple Myeloma

“…10,13,14). Moreover, the abnormal activation of these two pathways is associated with drug resistance and a poor prognosis of multiple myeloma (15)(16)(17). Nevertheless, previous studies have demonstrated that a sole inhibition of either the RAS/MAPK/ERK or PI3K/AKT pathways was not sufficiently efficacious to eradicate myeloma cells (10,16,(18)(19)(20)(21).…”

“…Moreover, the abnormal activation of these two pathways is associated with drug resistance and a poor prognosis of multiple myeloma (15)(16)(17). Nevertheless, previous studies have demonstrated that a sole inhibition of either the RAS/MAPK/ERK or PI3K/AKT pathways was not sufficiently efficacious to eradicate myeloma cells (10,16,(18)(19)(20)(21). The inhibition of RAS is only effective against myeloma cells with mutated RAS, whereas the inhibition of AKT results in compensative activation of the RAS/RAF/ERK pathway in myeloma cells (16,(22)(23)(24).…”

“…Nevertheless, previous studies have demonstrated that a sole inhibition of either the RAS/MAPK/ERK or PI3K/AKT pathways was not sufficiently efficacious to eradicate myeloma cells (10,16,(18)(19)(20)(21). The inhibition of RAS is only effective against myeloma cells with mutated RAS, whereas the inhibition of AKT results in compensative activation of the RAS/RAF/ERK pathway in myeloma cells (16,(22)(23)(24). These multifactorial and overlapping molecular mechanisms underlying tumorigenesis serve to make the molecular architecture of myeloma cells highly complex and heterogeneous among patients with multiple myeloma as well as even among subclones in a single patient, and thus, make it even more difficult to identify a universally effective therapeutic target in multiple myeloma.…”

Activity of everolimus (RAD001) in relapsed and/or refractory multiple myeloma: a phase I study

“…Notably, activation of the ToRC2 pathway by overexpression of DEP domain containing mTOR interacting protein (DEPTOR) 39 or activation of the ERK pathway may limit the dependency of PI3K and mToRC1. 40 The observed down-regulation of the The anti-angiogenic activity of rapalogues, via inhibition of vascular endothelial growth factor, also has to be taken into account. 42 The rate of adverse events was low in this highly pretreated group of patients suggesting that everolimus could potentially be combined with other drugs.…”

Endogenous transmembrane protein UT2 inhibits pSTAT3 and suppresses hematological malignancy

“…were from Abcam. AZD1480 (catalog S2162) (64)(65)(66)(67)(68), ruxolitinib (catalog S1378) (69)(70)(71), perifosine (catalog S1037) (72)(73)(74)(75)(76), and MK2206 (catalog S1078) (77)(78)(79) were purchased from Selleckchem. HEK293T, MDA-MB231, T47D, DU145, and PC3 cells were purchased from ATCC.…”