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

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Ubiquitin specific peptidase 7 (USP7) is a deubiquitinating enzyme (DUB) implicated in cancer progression through various substrates.
• Developing potent and selective USP7 inhibitors is challenging due to its multi-substrate nature and early inhibitors' limitations.
• Identifying biomarkers for USP7 inhibitor response is crucial for effective patient selection.

Purpose of the Study:

• To develop a novel, potent, and selective USP7 inhibitor.
• To elucidate the mechanism of action for selective USP7 inhibition in cancer cells.
• To identify predictive biomarkers for response to USP7-targeted therapy.

Main Methods:

• Structure-guided drug design and synthesis of XL177A, an irreversible USP7 inhibitor.
• Cellular assays to evaluate the effects of XL177A on cancer cell growth and gene expression.
• Transcriptome-wide analysis of p53 target genes and TP53 mutational status in ~500 cancer cell lines.

Main Results:

• XL177A irreversibly inhibits USP7 with sub-nanomolar potency and high selectivity.
• Selective USP7 inhibition by XL177A suppresses cancer cell growth via a p53-dependent pathway.
• Hotspot mutations in TP53, but not other genes, accurately predict response to XL177A across diverse cancer cell lines.
• TP53 knockout abrogated XL177A-induced growth suppression in TP53 wild-type cells.
• Ewing sarcoma and malignant rhabdoid tumors showed increased sensitivity to XL177A.

Conclusions:

• TP53 mutational status serves as a predictive biomarker for response to USP7 inhibition.
• XL177A represents a promising therapeutic agent for cancers with specific TP53 alterations.
• This study highlights the potential of targeting USP7 in specific cancer patient populations.