Sean Doyle (Emory University)| Ling Gu (Emory University)| Xiulei Mo (Emory University)| Andrey Ivanov (Emory University)| Qiankun Niu (Emory University)| Yuhong Du (Emory University)| Haian Fu (Emory University)
Comprehensive sequencing of patient tumors has revealed numerous recurrent mutations that are associated with tumorigenesis and tumor maintenance. These genomic abnormalities offer tumor-specific markers for personalized therapies. Leveraging such opportunities for therapeutic gains remains a major challenge, however. To address this gap, a quantitative screening platform was developed to identify mutation-specific neomorph protein-protein interactions for therapeutic interrogation. The screening platform detected novel neomorph interactions mediated by prominent recurrent point mutations in cancer-driver genes and suggested new oncogenic mechanisms for these cancer-drivers. As one example, prostate cancer-associated point mutations in the E3 ubiquitin ligase adaptor protein SPOP were found to induce protein-protein interactions with c-Jun, an oncogenic transcription factor. SPOP F133 mutations promote binding to c-Jun and upregulate c-Jun protein stability and transcriptional activity. SPOP F133-driven interactions with c-Jun may therefore provide a defined interface for pathway perturbation and represent a cancer target for prostate cancer patients with F133 mutations.
Support or Funding Information
This work was supported by the National Cancer Institute’s Office of Cancer Genomics Cancer Target Discovery and Development (CTD2) initiative (U01CA217875 to H.F.), the Georgia Research Alliance (Distinguished Investigator award to H.F.), and the Winship Cancer Institute (NIH 5P30CA138292). S.P.D. was supported by the NIH Pharmacological Sciences Training grant (4T32GM008602-20).