MK-2206, a Novel Allosteric Inhibitor of Akt, Synergizes with Gefitinib against Malignant Glioma via Modulating Both Autophagy and Apoptosis

Abstract

Gefitinib, a small molecule inhibitor of the epidermal growth factor receptor tyrosine kinase, has been shown to induce autophagy as well as apoptosis in tumor cells. Yet, how to exploit autophagy and apoptosis to improve therapeutic efficacy of this drug against cancer remains to be explored. We reported here that MK-2206, a potent allosteric Akt inhibitor currently in Phase I trials in patients with solid tumors, could reinforce the cytocidal effect of gefitinib against glioma. We found that co-treatment with gefitinib and MK-2206 increased the cytotoxicity of this growth factor receptor inhibitor in the glioma cells, and the Compusyn synergism/antagonism analysis showed that MK-2206 acted synergistically with gefitinib. The benefit of the combinatorial treatment was also demonstrated in an intracranial glioma mouse model. In the presence of MK-2206, there was a significant increase in apoptosis in glioma cells treated with gefitinib. MK-2206 also augmented the autophagy-inducing effect of gefitinib, as evidenced by increased levels of the autophagy marker, LC3-II. Inhibition of autophagy by silencing of the key autophagy gene, beclin 1 or 3-MA, further increased the cytotoxicity of this combinatorial treatment, suggesting that autophagy induced by these agents plays a cytoprotective role. Notably, at 48 hours following the combinatorial treatment, the level of LC3-II began to decrease but Bim was significantly elevated, suggesting a switch from autophagy to apoptosis. Based on the synergistic effect of MK-2206 on gefitinib observed in this study, the combination of these two drugs may be utilized as a new therapeutic regimen for malignant glioma.

Co-treatment of LY294002 or MK-2206 with AZD5363 Attenuates AZD5363-induced Increase in the Level of Phosphorylated AKT

“…For beneficial application purposes, we focused on clinically relevant inhibitors for co-treatment with AZD5363. Three known inhibitors MK-2206, wortmannin, and perifosine (17,18,(21)(22)(23)(24), were selected for co-treatment. We observed that the effect of MK-2206, wortmannin, and perifosine were similar to that of AZD5363, and LY294002, in reducing cellular growth and pGSK3β level in Hs578T cells ( Figure 3A and Figure 2C).…”

PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

“…MK2206 shows great potency against several cancer cell lines harboring pik3CA mutations [164,165] . In addition, MK-2206, in combination with other chemotherapeutic agents, exerts a greater potency against non-small cell lung cancer, glioma, breast, and ovarian carcinoma in both in vivo and in vitro models (Table 3) [166][167][168] . MK-2206 helps in restoring the efficacy of sorefenib to induce apoptosis in sorefenib-resistant hepatocellular carcinomas [169] .…”

Defective K-Ras oncoproteins overcome impaired effector activation to initiate leukemia in vivo

“…We exposed our T-ALL cell lines to inhibitors of PI3K (GDC-0941), 31 Akt (MK2206), 32 or MEK(PD0325901) 33 to determine whether their biochemical characteristics and/or the presence of third site mutations correlated with drug sensitivity. GDC-0941 efficiently reduced pAkt levels in T-ALL cell lines (supplemental Figure 6A) and blocked their growth ( Figure 5A).…”