MDM2 and MDM4 are therapeutic vulnerabilities in malignant rhabdoid tumors

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 CookJohn M. Krill-Burger, Aviad Tsherniak, Prafulla C. Gokhale, Peter J. Park, Kimberly Stegmaier, Loren D. Walensky, Charles W.M. Roberts, William C. Hahn

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

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 MRTs, 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 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 TP53 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.

Original languageEnglish (US)
Pages (from-to)2404-2414
Number of pages11
JournalCancer Research
Volume79
Issue number9
DOIs
StatePublished - 2019
Externally publishedYes

Bibliographical note

Funding Information:
A. Tsherniak is a consultant/advisory board member for Tango Therapeutics. K. Stegmaier reports receiving a commercial research grant from Novartis. L.D. Walensky is a consultant/advisory board member for Aileron Therapeutics and has ownership interest (including stocks and patents) in Aileron Therapeutics. W.C. Hahn reports receiving a commercial research grant from Deerfield, has ownership interest (including stocks and patents) in KSQ Therapeutics, and is a consultant/advisory board member for Thermo Fisher Scientific, Paraxel, AjuIB, KSQ Therapeutics, and MPM. No potentialconflictsof interest weredisclosedby the other authors.

Funding Information:
The authors thank the Roberts, Hahn, and Cichowski labs, and Pediatric Dependencies Project for insightful discussions. The authors thank Roche for providing formulated idasanutlin for in vivo studies, Daniel Bauer for advice on sgRNA design, and Sayalee Potdar and Jake Kloeber for assistance with Illumina sequencing. The authors thank John Daley for assistance with flow cytometry and Franck Bordeaut, Yoon-Jae Cho, C. David James, Yasumichi Kuwahara, Timothy Triche, Geoffrey Wahl, and Bernard Weissman for cell lines. This work was supported by U.S. NIH grants T32GM007753 (to T.P. Howard and A.M. Morgan), T32GM007226 (to T.P. Howard), R00CA197640 (to X. Wang), P50CA101942 (to A.L. Hong), T32CA136432 (to N.V. Dharia), F30CA221087 (to A.M. Morgan), 1R50CA211399 (to G.H. Bird), R35CA210030 (to K. Stegmaier), U01CA176058 (to W.C. Hahn), R01CA172152 (to C.W.M. Roberts), and R01CA113794 (to C.W.M. Roberts); ACS Mentored Research Scholar Grant 132943-MRSG-18-202-01-TBG (to A.L. Hong), St. Baldrick's Robert J. Arceci Award (to K. Stegmaier), Hyundai Hope on Wheels Quantum Award (to L.D. Walensky), Alex's Lemonade Stand REACH Grant (to L.D. Walensky), Cure AT/RT Now (to C.W.M. Roberts), Avalanna Fund (to C.W. M. Roberts), Garrett B. Smith Foundation (to C.W.M. Roberts), and ALSAC/St. Jude (to C.W.M. Roberts). This work is partially based upon data generated by the Cancer Target Discovery and Development (CTD2) Network (https://ocg. cancer.gov/programs/ctd2/data-portal) and the TARGET initiative (http://ocg. cancer.gov/programs/target).

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