AI Article Synopsis

  • FBXW7 is a protein that helps break down other proteins, and when it's mutated, it can contribute to cancer.
  • Scientists used a special tool called CRISPR to change certain parts of this protein in colon tissue samples, which made the samples grow better without needing as much EGF, a growth factor.
  • The research showed that these mutations help keep another protein called EGFR alive longer, making the cancer cells less sensitive to certain treatments.

Article Abstract

FBXW7 is an E3 ubiquitin ligase that targets proteins for proteasome-mediated degradation and is mutated in various cancer types. Here, we use CRISPR base editors to introduce different hotspot mutations in human colon organoids. Functionally, mutation reduces EGF dependency of organoid growth by ~10,000-fold. Combined transcriptomic and proteomic analyses revealed increased EGFR protein stability in mutants. Two distinct phosphodegron motifs reside in the cytoplasmic tail of EGFR. Mutations in these phosphodegron motifs occur in human cancer. CRISPR-mediated disruption of the phosphodegron motif at T693 reduced EGFR degradation and EGF growth factor dependency. mutant organoids showed reduced sensitivity to EGFR-MAPK inhibitors. These observations were further strengthened in CRC-derived organoid lines and validated in a cohort of patients treated with panitumumab. Our data imply that FBXW7 mutations reduce EGF dependency by disabling EGFR turnover.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10962967PMC
http://dx.doi.org/10.1073/pnas.2309902121DOI Listing

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