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Inhibition of wild-type p53-expressing AML by the novel small molecule HDM2 inhibitor CGM097

Weisberg, Ellen and Halilovic, Ensar and Cooke, Vesselina and Nonami, Atsushi and Ren, Tao and Sanda, Takaomi and Simkin, Irene and Yuan, Jing and Antonakos, Brandon and Barys, Louise and Ito, Moriko and Cowens, Kristen and Nelson, Erik and Sattler, Martin and Jeay, Sebastien and Wuerthner, Jens U. and McDonough, Sean M. and Wiesmann, Marion and Griffin, James D. (2015) Inhibition of wild-type p53-expressing AML by the novel small molecule HDM2 inhibitor CGM097. Molecular Cancer Therapeutics, 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 HDM2 protein binds to p53 and blocks its activity. Inhibition of HDM2:p53 interaction activates p53 and causes apoptosis or cell-cycle arrest. Here, we investigated the ability of the novel HDM2 inhibitor CGM097 to potently and selectively kill WT p53-expressing AML cells. The antileukemic effects of CGM097 were studied using cellbased proliferation assays (human AML cell lines, primary AML patient cells, and normal bone marrow samples), apoptosis, and cell-cycle assays, ELISA, immunoblotting, and an AML patient-derived in vivo mouse model. CGM097 potently and selectively inhibited the proliferation of human AML cell lines and the majority of 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 oncogenic FLT3-expressing cells cultured both in the absence as well as the presence of cytoprotective stromal-secreted cytokines, as well as when combined with MEK inhibition in cells with activated MAPK signaling. Finally, CGM097 was effective in reducing leukemia burden in vivo. These data suggest that CGM097 is a promising treatment for AML characterized as harboring WT p53 as a single agent, as well as in combination with other therapies targeting oncogene-activated pathways that drive AML.

Item Type: Article
Date Deposited: 29 Nov 2017 00:45
Last Modified: 25 Jan 2019 00:45
URI: https://oak.novartis.com/id/eprint/25475

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