CSIG-01. EGFR AND AXL RECEPTOR TYROSINE KINASES DRIVE ONCOGENESIS BY LZTR1 MUTATION
نویسندگان
چکیده
Abstract LZTR1, the substrate-specific adaptor of a CUL3-dependent ubiquitin ligase is among most frequently mutated coding gene in syndromic and sporadic human cancers including glioblastoma multiforme, which approximately 27% cases harbor inactivating mutations copy number loss. However, both identity protein substrates targeted by LZTR1-mediated ubiquitylation biological contexts regulated specific LZTR1-substrate(s) interactions remain uncertain. Here, we combined biochemical genetic studies to identify LZTR1 interrogated their tumor-driving function context loss-of-function new conditional Lztr1 knockout mouse. Multiple screens converged on receptor tyrosine kinases EGFR AXL as interactors for ubiquitin-dependent degradation lysosome LZTR1-CUL3 complexes. Pathogenic affecting failed promote tumors. Mice harboring deletion with loss CDKN2A neural progenitor compartment generated peripheral nervous system tumors schwannoma like malignant (MPNST). Tumors from LZTR1-mutant mouse model accumulated very high levels exhibited potent vulnerability combinatorial inhibition kinases. These findings explain mechanism tumorigenesis associated inactivation offer therapeutic strategy patients affected carrying LZTR1.
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ژورنال
عنوان ژورنال: Neuro-oncology
سال: 2022
ISSN: ['1523-5866', '1522-8517']
DOI: https://doi.org/10.1093/neuonc/noac209.150