Thomas P Howard, Taylor E Arnoff, Melinda R Song, Andrew O Giacomelli, Xiaofeng Wang, Andrew L Hong, Neekesh V Dharia, Su Wang, Francisca Vazquez, Minh-Tam Pham, Ann M Morgan, Franziska Wachter, Gregory H Bird, Guillaume Kugener, Elaine M Oberlick, Matthew G Rees, Hong L Tiv, Justin H Hwang, Katherine H Walsh, April Cook, John M Krill-Burger, Aviad Tsherniak, Prafulla C Gokhale, Peter J Park, Kimberly Stegmaier, Loren D Walensky, William C Hahn, Charles W M Roberts
Malignant rhabdoid tumors (MRT) are highly aggressive pediatric cancers that respond poorly to current therapies. In this study, we screened several MRT cell lines with large-scale RNAi, CRISPR-Cas9, and small-molecule libraries to identify potential drug targets specific for these cancers. We discovered MDM2 and MDM4, the canonical negative regulators of p53, as significant vulnerabilities. Using two compounds currently in clinical development, idasanutlin (MDM2-specific) and ATSP-7041 (MDM2/4-dual), we show that MRT cells were more sensitive than other p53 wild-type cancer cell lines to inhibition of MDM2 alone as well as dual inhibition of MDM2/4...
February 12, 2019: Cancer Research