Weisberg, Ellen, Halilovic, Ensar, Cooke, Vesselina, Nonami, Atsushi, Ren, Tao, Sanda, Takaomi, Simkin, Irene, Yuan, Jing, Antonakos, Brandon, Barys, Louise, Ito, Moriko, Cowens, Kristen, Nelson, Erik, Sattler, Martin, Jeay, Sebastien, Wuerthner, Jens, McDonough, Sean, Wiesmann, Marion and Griffin, James (2015) Inhibition of wild-type p53-expressing AML by novel small molecule HDM2 inhibitor, CGM097. Mol Cancer Ther, 14 (10). pp. 2249-2259. ISSN 1538-8514

Abstract

The tumor suppressor, p53, is a key regulator of apoptosis and functions upstream in the apoptotic cascade by both indirectly and directly regulating Bcl-2 family proteins. In cells expressing wild-type (wt) p53, the Human Double Minute 2 (HDM2) protein binds to p53 and blocks its activity. Inhibition of HDM2:p53 interaction activates p53 and causes apoptosis or cell cycle arrest. We have characterized the novel HDM2 inhibitor, CGM097, as having significant activity against wt p53-expressing acute myeloid leukemia (AML). Specifically, CGM097 potently and selectively inhibited the proliferation of human AML cell lines and primary AML cells expressing wt p53, but not mutant p53, in a target-specific manner. Several patient samples that harbored mutant p53 were comparatively unresponsive to CGM097. Synergy was observed when CGM097 was combined with FLT3 inhibition against mutant FLT3-expressing cells, as well as when combined with MEK inhibition in cells with activated MAPK signaling. Finally, CGM097 was effective in reducing leukemia burden in vivo. Taken together, these data suggest that CGM097 might be a promising treatment for AML characterized as harboring wt p53 as a single agent, as well as possibly in combination with another targeted therapy using tyrosine kinase inhibitors (TKIs) against oncogenes that drive AML.

Item Type:	Article
Date Deposited:	07 Jun 2016 23:45
Last Modified:	07 Jun 2016 23:45
URI:	https://oak.novartis.com/id/eprint/25186