Selective USP7 inhibition elicits cancer cell killing through a p53-dependent mechanism

Schauer, Nathan J.; Liu, Xiaoxi; Magin, Robert S.; Doherty, Laura M.; Chan, Wai Cheung; Ficarro, Scott B.; Hu, Wanyi; Roberts, Rebekka M.; Iacob, Roxana E.; Stolte, Björn; Giacomelli, Andrew O.; Perera, Sumner; McKay, Kyle; Boswell, Sarah A.; Weisberg, Ellen L.; Ray, Arghya; Chauhan, Dharminder; Dhe-Paganon, Sirano; Anderson, Ken C.; Griffin, James D.; Li, Jianing; Hahn, William C.; Sorger, Peter K.; Engen, John R.; Stegmaier, Kimberly; Marto, Jarrod A. und Buhrlage, Sara J. (2020): Selective USP7 inhibition elicits cancer cell killing through a p53-dependent mechanism. In: Scientific Reports, Bd. 10, Nr. 1, 5324

Abstract

Ubiquitin specific peptidase 7 (USP7) is a deubiquitinating enzyme (DUB) that removes ubiquitin tags from specific protein substrates in order to alter their degradation rate and sub-cellular localization. USP7 has been proposed as a therapeutic target in several cancers because it has many reported substrates with a role in cancer progression, including FOXO4, MDM2, N-Myc, and PTEN. The multisubstrate nature of USP7, combined with the modest potency and selectivity of early generation USP7 inhibitors, has presented a challenge in defining predictors of response to USP7 and potential patient populations that would benefit most from USP7-targeted drugs. Here, we describe the structureguided development of XL177A, which irreversibly inhibits USP7 with sub-nM potency and selectivity across the human proteome. Evaluation of the cellular effects of XL177A reveals that selective USP7 inhibition suppresses cancer cell growth predominantly through a p53-dependent mechanism: XL177A specifically upregulates p53 transcriptional targets transcriptome-wide, hotspot mutations in TP53 but not any other genes predict response to XL177A across a panel of similar to 500 cancer cell lines, and TP53 knockout rescues XL177A-mediated growth suppression of TP53 wild-type (WT) cells. Together, these findings suggest TP53 mutational status as a biomarker for response to USP7 inhibition. We find that Ewing sarcoma and malignant rhabdoid tumor (MRT), two pediatric cancers that are sensitive to other p53-dependent cytotoxic drugs, also display increased sensitivity to XL177A.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 2045-2322
• Sprache: Englisch