2022 World Conference on Lung Cancer (Posters)-P2.14-03. Restored Ubiquitination and Degradation of Exon 14 Skipped MET with Proteolysis Targeting Chimeras

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The Mayo Foundation for Medical Education and Research has developed a new strategy to inhibit and eliminate an oncogenic driver called hepatocyte growth factor receptor (MET) in multiple malignancies. MET is known to drive cancer growth and is particularly relevant in non-small cell lung cancers that have mutations in MET exon 14 skipping. These mutations lead to the production of a shortened MET protein without its juxtamembrane domain, which allows MET to evade degradation and continue driving cancer growth. <br /><br />To address this issue, the researchers developed MET-targeting proteolysis targeting chimeras (PROTACs), which are molecules that link a MET-targeting component with an E3 ubiquitin-protein ligase component. The PROTACs recruit the E3 ligase to MET and promote its degradation by the proteasome. The researchers synthesized several MET-targeting PROTACs and screened them for their ability to degrade MET in various cell lines and cancer models.<br /><br />The top candidate, called PROTAC 48-284, showed potent degradation of MET with exon 14 skipping mutation in live cell imaging and subsequent analysis. This degradation was confirmed by mass spectrometry and Western blotting. The PROTAC also showed degradation of MET in a xenograft model and a 3D patient-derived micro-cancer model with a different MET fusion.<br /><br />Overall, the study demonstrates that MET-targeting PROTACs can restore the ubiquitination and degradation of MET with exon 14 skipping mutations. This approach may have therapeutic potential for cancers with MET alterations. Further research can explore the efficacy of MET-targeting PROTACs in preclinical and clinical settings for the treatment of MET-driven cancers.

Asset Subtitle

Aaron Mansfield, United States

Meta Tag

Speaker Aaron Mansfield, United States

Topic Tumour Biology and Biomarkers - Molecular Profiling and Targeted Therapeutics

Keywords

Mayo Foundation for Medical Education and Research

oncogenic driver

hepatocyte growth factor receptor

MET

non-small cell lung cancers

MET exon 14 skipping

MET-targeting proteolysis targeting chimeras

PROTACs

E3 ubiquitin-protein ligase

ubiquitination and degradation