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Cancer Res DOI:10.1158/0008-5472.CAN-18-3066

MDM2 and MDM4 are Therapeutic Vulnerabilities in Malignant Rhabdoid Tumors.

Publication TypeJournal Article
Year of Publication2019
AuthorsHoward, TP, Arnoff, TE, Song, MR, Giacomelli, AO, Wang, X, Hong, AL, Dharia, NV, Wang, S, Vazquez, F, Pham, M-T, Morgan, AM, Wachter, F, Bird, GH, Kugener, G, Oberlick, EM, Rees, MG, Tiv, HL, Hwang, JH, Walsh, KH, Cook, A, Krill-Burger, JM, Tsherniak, A, Gokhale, PC, Park, PJ, Stegmaier, K, Walensky, LD, Hahn, WC, Roberts, CWM
JournalCancer Res
Date Published2019 Feb 12
ISSN1538-7445
Abstract

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. These compounds caused significant upregulation of the p53 pathway in MRT cells, and sensitivity was ablated by CRISPR-Cas9-mediated inactivation of TP53. We show that loss of SMARCB1, a subunit of the SWI/SNF (BAF) complex mutated in nearly all MRT, sensitized cells to MDM2 and MDM2/4 inhibition by enhancing p53-mediated apoptosis. Both MDM2 and MDM2/4 inhibition slowed MRT xenograft growth in vivo, with a five-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 p53 and provide preclinical evidence to support the targeting of MDM2 and MDM4 in this often-fatal pediatric cancer.

DOI10.1158/0008-5472.CAN-18-3066
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/30755442?dopt=Abstract

Alternate JournalCancer Res.
PubMed ID30755442
Grant ListR00 CA197640 / CA / NCI NIH HHS / United States
R01 CA113794 / CA / NCI NIH HHS / United States
U01 CA176058 / CA / NCI NIH HHS / United States
P30 CA021765 / CA / NCI NIH HHS / United States
R01 CA172152 / CA / NCI NIH HHS / United States