2. Academic Validation
  3. USP7 V517F mutation as a mechanism of inhibitor resistance

USP7 V517F mutation as a mechanism of inhibitor resistance

  • Nat Commun. 2025 Mar 14;16(1):2526. doi: 10.1038/s41467-025-56981-w.
Yu-Ling Miao # 1,  Fengying Fan # 2 3,  Yong-Jun Cheng # 1,  Li Jia 1 3,  Shan-Shan Song 1 3,  Xia-Juan Huan 1 3,  Xu-Bin Bao 1 3,  Jian Ding 1 3,  Xuekui Yu 4 5,  Jin-Xue He 6 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China.
  • 2 State Key Laboratory of Drug Research, Cryo-Electron Microscopy Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China.
  • 3 University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China.
  • 4 State Key Laboratory of Drug Research, Cryo-Electron Microscopy Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China. xkyu@simm.ac.cn.
  • 5 University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China. xkyu@simm.ac.cn.
  • 6 State Key Laboratory of Drug Research, Cancer Research Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China. jinxue_he@simm.ac.cn.
  • 7 University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China. jinxue_he@simm.ac.cn.
  • # Contributed equally.
PMID: 40087304 DOI: 10.1038/s41467-025-56981-w
Abstract

Anticipating and addressing resistance is essential for maximizing the potential of an oncology target and effectively addressing clinical needs. In this study, we aimed to proactively outline the resistance mechanisms of USP7 inhibitors. We discovered a key treatment-emergent heterozygous mutation (V517F) in USP7 in the binding pocket of compounds as the primary cause of resistance to the USP7 Inhibitor USP7-797. Our structural analysis, supported by AlphaFold2 predictions, indicates that the V517F mutation altered the conformation of the compound binding pocket, causing steric hindrance and reducing the affinity between USP7 and its inhibitors. Consistent with these predictions, the affinity between V517F mutant and USP7 inhibitors was found to reduce significantly. Conversely, substitutions at position V517 with smaller side chains, such as V517G, V517A, and V517I, do not significantly impact binding affinity. In contrast, replacement with the bulkier side chain V517Y leads to reduced binding affinity and diminished inhibitor efficacy. Furthermore, the engineered cell lines harboring the V517F mutation exhibited substantial resistance to USP7 inhibition. These data provide rationales for patient selection and the development of next-generation USP7 inhibitors designed to overcome treatment-emergent mutations.

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