Ubiquitin-specific protease 7-mediated stabilization of discoidin domain receptor 1 drives progression of TP53-Mutant cancers.

Receptor tyrosine kinase DDR1 (Discoidin Domain Receptor 1) interacts with the extracellular matrix (ECM) to promote tumor cell proliferation through its intracellular kinase activity, while its extracellular non-enzymatic domain creates a physical barrier for immune evasion. Although DDR1 inhibitors and antibodies have been developed, targeting DDR1 kinase activity alone cannot fully block the biological effects mediated by its scaffold function. Therefore, developing DDR1 degraders presents a potentially more effective therapeutic strategy. Through screening a proprietary small-molecule ubiquitination library, we identified NSC632839, which significantly induces DDR1 protein degradation. Mechanistically, chemical proteomics and genetic studies demonstrated that NSC632839 functions by inhibiting USP7, which interacts with, stabilizes, and deubiquitinates DDR1, preventing its proteasomal degradation. Importantly, we observed that TP53 loss or mutation in tumor cells and clinical samples markedly upregulates DDR1 expression, thereby enhancing its interaction with USP7. Inhibition of USP7 with NSC632839 or other selective inhibitors restores TP53 expression, resulting in a significant reduction in DDR1 levels. In various preclinical models, targeting USP7 with NSC632839 effectively eliminates tumor cells, offering a promising therapeutic strategy to overcome tumor relapse driven by TP53 mutations, both in vitro and in vivo. This study highlights the potential of DDR1 degradation via USP7 inhibition as a novel approach to treat TP53 mutation-enriched tumors.