Somatic gain-of-function mutations in BUD13 promote oncogenesis by disrupting Fbw7 function
Abstract
Somatic mutations occurring on key enzymes are extensively studied and targeted therapies are developed with clinical promises. However, context-dependent enzyme function through distinct substrates complicated targeting a given enzyme. Here, we develop an algorithm to elucidate a new class of somatic mutations occurring on enzyme-recognizing motifs that cancer may hijack to facilitate tumorigenesis. We validate BUD13-R156C and -R230Q mutations evading RSK3-mediated phosphorylation with enhanced oncogenicity in promoting colon cancer growth. Further mechanistic studies reveal BUD13 as an endogenous Fbw7 inhibitor that stabilizes Fbw7 oncogenic substrates, while cancerous BUD13-R156C or -R230Q interferes with Fbw7Cul1 complex formation. We also find this BUD13 regulation plays a critical role in responding to mTOR inhibition, which can be used to guide therapy selections. We hope our studies reveal the landscape of enzyme-recognizing motif mutations with a publicly available resource and provide novel insights for somatic mutations cancer hijacks to promote tumorigenesis with the potential for patient stratification and cancer treatment.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jun 29, 2023
- Source ID
- 10.1084/jem.20222056
Entities
People
- Jianfeng Chen
- Pengda Liu
- Xianming Tan
- Xinyi Zhang
Organizations
- Congressionally Directed Medical Research Programs
- Gabrielle’s Angel Foundation for Cancer Research
- National Institutes of Health
- North Carolina Biotechnology Center
- University of North Carolina at Chapel Hill