Conflict of interest: Nothing to declare.
Testing of the Akt/PKB inhibitor MK-2206 by the pediatric preclinical testing program†
Article first published online: 18 NOV 2011
Copyright © 2011 Wiley Periodicals, Inc.
Pediatric Blood & Cancer
Volume 59, Issue 3, pages 518–524, September 2012
How to Cite
Gorlick, R., Maris, J. M., Houghton, P. J., Lock, R., Carol, H., Kurmasheva, R. T., Kolb, E. A., Keir, S. T., Reynolds, C. P., Kang, M. H., Billups, C. A. and Smith, M. A. (2012), Testing of the Akt/PKB inhibitor MK-2206 by the pediatric preclinical testing program. Pediatr. Blood Cancer, 59: 518–524. doi: 10.1002/pbc.23412
- Issue published online: 12 JUL 2012
- Article first published online: 18 NOV 2011
- Manuscript Accepted: 4 OCT 2011
- Manuscript Received: 6 AUG 2011
- National Cancer Institute. Grant Numbers: NO1-CM-42216, CA21765, CA108786
- developmental therapeutics;
- preclinical testing
MK-2206 is a small molecule allosteric inhibitor of Akt/PKB that is undergoing clinical trials for treatment of cancer.
MK-2206 was tested against the PPTP in vitro panel using a 96-hour exposure (1.0 nM–10 µM), and in vivo using thrice weekly dosing for a planned 4 weeks at its maximum tolerated dose (MTD) of 180 mg/kg.
In vitro, the median relative IC50 value for MK-2206 was 2.2 µM. Four cell lines with IC50 values < 200 nM included two ALL cell lines (COG-LL-317 and RS4;11), an AML cell line with an activating KIT mutation (Kasumi-1), and a Ewing sarcoma cell line (CHLA-10). In vivo, MK-2206 induced significant differences in EFS distribution compared to control in 12 of 29 (41%) of the evaluable solid tumor xenografts and in 2 of 8 (25%) of the evaluable ALL xenografts. Significant differences in EFS distribution were most frequently noted in the osteosarcoma panel (6 of 6). A single solid tumor xenograft (OS-31) had a greater than twofold increase in time to event compared to control animals, with all other solid tumor xenografts showing lesser degrees of tumor growth inhibition. Objective responses were not observed for either the solid tumor or ALL xenografts.
MK-2206 showed its most consistent activity in vitro against ALL cell lines and in vivo against osteosarcoma xenografts. However, no objective responses were observed in solid tumor or ALL xenografts. Further preclinical work evaluating MK-2206 in pediatric models in the combination therapy setting may contribute to its pediatric development. Pediatr Blood Cancer 2012;59:518–524. © 2011 Wiley Periodicals, Inc.