Published online Oct 10, 2016. doi: 10.5306/wjco.v7.i5.352
Peer-review started: March 24, 2016
First decision: May 16, 2016
Revised: June 25, 2016
Accepted: July 29, 2016
Article in press: August 1, 2016
Published online: October 10, 2016
Processing time: 199 Days and 14.5 Hours
The Akt signal transduction pathway controls most hallmarks of cancer. Activation of the Akt cascade promotes a malignant phenotype and is also widely implicated in drug resistance. Therefore, the modulation of Akt activity is regarded as an attractive strategy to enhance the efficacy of cancer therapy and irradiation. This pathway consists of phosphatidylinositol 3 kinase (PI3K), mammalian target of rapamycin, and the transforming serine-threonine kinase Akt protein isoforms, also known as protein kinase B. DNA-targeted agents, such as platinum agents, taxanes, and antimetabolites, as well as radiation have had a significant impact on cancer treatment by affecting DNA replication, which is aberrantly activated in malignancies. However, the caveat is that they may also trigger the activation of repairing mechanisms, such as upstream and downstream cascade of Akt survival pathway. Thus, each target can theoretically be inhibited in view of improving the potency of conventional treatment. Akt inhibitors, e.g., MK-2206 and perifosine, or PI3K modulators, e.g., LY294002 and Wortmannin, have shown some promising results in favor of sensitizing the cancer cells to the therapy in vitro and in vivo, which have provided the rationale for incorporation of these novel agents into multimodality treatment of different malignancies. Nevertheless, despite the acceptable safety profile of some of these agents in the clinical studies, with regard to the efficacy, the results are still too preliminary. Hence, we need to wait for the upcoming data from the ongoing trials before utilizing them into the standard care of cancer patients.
Core tip: The Akt pathway plays an important role in resistance to several cytotoxic agents, targeted drugs and radiation. Exposure to these drugs will stimulate the Akt survival pathway leading to a decreased response to these drugs. In model systems inhibition of the Akt pathway enhanced the cytotoxicity of drugs like taxanes, antimetabolites, platinum analogs, several targeted drugs and radiation. Akt inhibitors offer a new opportunity to increase the efficacy of currently used drugs and of radiotherapy.