Journal
CANCER CELL
Volume 18, Issue 5, Pages 411-422Publisher
CELL PRESS
DOI: 10.1016/j.ccr.2010.10.024
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Funding
- NCI [1K22CA128886]
- NIH [5P01CA92625, CA61449, CA100845]
- Todd J. Schwartz Pediatric Oncology Fund
- Burroughs Wellcome Fund
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Cancer cells neutralize p53 by deletion, mutation, proteasomal degradation, or sequestration to achieve a pathologic survival advantage. Targeting the E3 ubiquitin ligase HDM2 can lead to a therapeutic surge in p53 levels. However, the efficacy of HDM2 inhibition can be compromised by overexpression of HDMX, an HDM2 homolog that binds and sequesters p53. Here, we report that a stapled p53 helix preferentially targets HDMX, blocks the formation of inhibitory p53-HDMX complexes, induces p53-dependent transcriptional upregulation, and thereby overcomes HDMX-mediated cancer resistance in vitro and in vivo. Importantly, our analysis of p53 interaction dynamics provides a blueprint for reactivating the p53 pathway in cancer by matching HDM2, HDMX, or dual inhibitors to the appropriate cellular context.
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