MK-2206 synergizes with the Mek inhibitor U0126 and the drug combination leads to increased inhibition of mTOR activity.

When MK-2206 was combined with the Mek1/2 inhibitor U0126, synergistic cytotoxicity was observed A) in cell lines sensitive to MK-2206 (MM1S, MM1R and OPM2) and B) in cell lines less sensitive to MK-2206 (RPMI8226, DOX40 and U266) as a single agent as measured using the MTT assay. The graph represents the concentrations of MK-2206, U0126 or the combination at which maximum synergy was observed. The concentrations are: 1) MM1S−0.5 µM MK-2206, 10 µM U0126, 2) MM1R−0.5 µM MK-2206, 10 µM U0126 and 3) OPM2−1 µM MK-2206, 20 µM U0126. 4) RPMI8226−2.5 µM MK-2206, 10 µM U0126, 5) DOX40−5 µM MK-2206, 20 µM U0126 and 6) U266−5 µM MK-2206, 30 µM U0126. Cell lines used are indicated on the X-axis and Viability (% of control) indicated on the Y-axis. Error bars represent standard deviation. C) MM1S cells were left untreated or treated with U0126 (10 µM) for 24 hrs. Following this, cells were treated with 2.5 µM of MK-2206 for 1, 2, 4 or 8 hrs. As a control, MM1S cells were treated with U0126 alone (10 µM) for 32 hrs or MK-2206 alone (2.5 µM) for 8 hrs. We observed significant down regulation of pAkt and other downstream members of the pathway and pErk when MK-2206 was used in combination with U0126 with no difference in total proteins and actin, which serve as loading controls.