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

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 multi-substrate 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 structure-guided 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 ~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.

Citation

Nathan J Schauer, Xiaoxi Liu, Robert S Magin, Laura M Doherty, Wai Cheung Chan, Scott B Ficarro, Wanyi Hu, Rebekka M Roberts, Roxana E Iacob, Björn Stolte, Andrew O Giacomelli, Sumner Perera, Kyle McKay, Sarah A Boswell, Ellen L Weisberg, Arghya Ray, Dharminder Chauhan, Sirano Dhe-Paganon, Ken C Anderson, James D Griffin, Jianing Li, William C Hahn, Peter K Sorger, John R Engen, Kimberly Stegmaier, Jarrod A Marto, Sara J Buhrlage. Selective USP7 inhibition elicits cancer cell killing through a p53-dependent mechanism. Scientific reports. 2020 Mar 24;10(1):5324

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PMID: 32210275

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