MK-2206, as an Akt Inhibitor, enhances antitumor efficacy by chemotherapeutic agents

Development and maintenance of many tumors have been reported to be associated with abnormal activation of PI3K. Akt is a critical downstream factor of PI3K signaling pathway and is important in promoting cell survival and inhibiting apoptosis. Clinically, Akt activation and overexpression is often associated with resistance to chemotherapy or radiotherapy. Thus, clinically available small-molecule inhibitors of Akt have remarkable potential in cancer treatment.
MK-2206 is an orally active allosteric Akt inhibitor that has been approved to used for the treatment of solid tumors. Biochemical assay shows that MK-2206 has a higher inhibition against AKT1 and AKT2 than AKT3.
     In the latest paper published on Molecular Cancer Therapeutics, Hirai et al. explore the effects of MK-2206 in combination with several anticancer agents. The treatment of MK-2206 or EGFR inhibitor erlotinib respectively causes growth inhibition on strong>non–small-cell lung cancer (NSCLC) and skin epidermoid cell lines, and the further combination of MK-2206 and erlotinib also shows a synergistic effect both on sensitive and insensitive cells. Subsequently, the combination is observed to induce apoptosis by caspase activation. Just like the results in vitro, the combination of MK-2206 and erlotinib exhibits significantly greater antitumor effects than agent alone in vivo. MK-2206
also shows synergistic responses in combination with other EGFR inhibitors or cytotoxic agents, such as lapatinib and docetaxel[1].
     Taken together, the combination of MK-2206 and other anti-tumor agents indeed has a greater efficacy on cancers than monotherapy, thus MK-2206 is a potential agent to elavate the treatment of cancer patients.

References
[1]. Mol Cancer Ther; 2010; 9(7); 1956–67.

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