Abstract 594: Dual regulation of cell death by Akt kinase inhibitor Mk-2206 in colorectal cancer.
Authors: Agarwal Ekta , Chaudhuri Anathbandhu , Brattain Michael G. , Chowdhury Sanjib 
Published: August 2014

Background: Colorectal cancer (CRC) is the second highest cause of cancer related deaths in the United States. Dissemination of CRC cells to distant organs (liver and lungs) often leads to treatment failure. Thus, the identification of novel strategies for the treatment of metastases is a pressing need in this type of cancer. Several reports have suggested the development of inappropriate cell survival signaling for various steps in the metastatic process and have noted the particular importance of aberrant cell survival to successful colonization at metastatic sites. We have earlier reported that Akt inactivation is associated with survivin and XIAP downregulation and increased cell death. Given the widespread role of Akt in cell survival and association of survivin and XIAP with CRC progression and metastasis, as well as other types of cancer, we hypothesize that Akt phosphorylation may be key to the aberrant survival mechanism permitting metastatic growth at distal organ sites. Thus, inactivation of Akt activity might be an important therapeutic target in CRC metastasis.

Methods: Mk-2206 is a potent allosteric kinase inhibitor of Akt (provided by Merck). It inhibits the translocation of Akt to plasma membrane to prevent its phosphorylation and activation. IGF1R dependent CRC cell lines were treated with MK-2206 to study its anti-tumor effects in vitro and in vivo.

Results: Mk-2206 promotes anti-tumor activity in the IGF1R dependent CRC cell lines and increases cell death both in vitro and in vivo. Mk-2206 inhibits Akt phosphorylation at S473 and T308 leading to decreased protein expression of XIAP and Survivin. Interestingly, Mk-2206 treatment upregulated apoptosis inducing factor (AIF) and its translocation from mitochondria to the nucleus and a concomitant inactivation of phospho-Ezrin at Y354 and T567.Ezrin is a cytoskeleton organizing protein implicated in the metastatic process of several other types of cancer in addition to CRC. RNAi studies were performed to confirm the role of AIF and Ezrin in Mk-2206 mediated cell death. We are currently analyzing the anti-metastatic effects of MK-2206 in an orthotopic mouse model of human CRC cells.

Conclusion: In this work we have demonstrated the effectiveness of Mk-2206 as a pharmacological agent for targeting CRC cells. We have identified dual mechanisms by which Mk-2206-mediated Akt inactivation promotes cell death.The first mechanism involved caspase-independent AIF mediated DNA fragmentation; while the second involved caspase-dependent Akt-Ezrin-XIAP mediated cell death.

Citation Format: Ekta Agarwal, Anathbandhu Chaudhuri, Michael G. Brattain, Sanjib Chowdhury. Dual regulation of cell death by Akt kinase inhibitor Mk-2206 in colorectal cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 594. doi:10.1158/1538-7445.AM2013-594

Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.