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Howard, Thomas P; Arnoff, Taylor E; Song, Melinda R; Giacomelli, Andrew O; Wang, Xiaofeng; Hong, Andrew L; Dharia, Neekesh V; Wang, Su; Vazquez, Francisca; Pham, Minh-Tam; Morgan, Ann M; Wachter, Franziska; Bird, Gregory H; Kugener, Guillaume; Oberlick, Elaine M; Rees, Matthew G; Tiv, Hong L; Hwang, Justin H; Walsh, Katherine H; Cook, April; Krill-Burger, John M; Tsherniak, Aviad; Gokhale, Prafulla C; Park, Peter J; Stegmaier, Kimberly; Walensky, Loren D; Hahn, William C; Roberts, Charles W M
Cancer research, 05/2019, Letnik: 79, Številka: 9Journal Article
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 and , 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. These compounds caused significant upregulation of the p53 pathway in MRT cells, and sensitivity was ablated by CRISPR-Cas9-mediated inactivation of . We show that loss of SMARCB1, a subunit of the SWI/SNF (BAF) complex mutated in nearly all MRTs, sensitized cells to MDM2 and MDM2/4 inhibition by enhancing p53-mediated apoptosis. Both MDM2 and MDM2/4 inhibition slowed MRT xenograft growth , with a 5-day idasanutlin pulse causing marked regression of all xenografts, including durable complete responses in 50% of mice. Together, these studies identify a genetic connection between mutations in the SWI/SNF chromatin-remodeling complex and the tumor suppressor gene and provide preclinical evidence to support the targeting of MDM2 and MDM4 in this often-fatal pediatric cancer. SIGNIFICANCE: This study identifies two targets, MDM2 and MDM4, as vulnerabilities in a deadly pediatric cancer and provides preclinical evidence that compounds inhibiting these proteins have therapeutic potential.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Povezave do osebnih bibliografij avtorjev | Povezave do podatkov o raziskovalcih v sistemu SICRIS |
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Vir: Osebne bibliografije
in: SICRIS
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