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Updated: Jul 1, 2025
Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation
Published on: May 20, 2020
Epidermal growth factor receptor (EGFR) is a target of the tumor-suppressor E3 ligase FBXW7
Matteo Boretto1, Maarten H Geurts1, Shashank Gandhi1,2
1Organoid group, Oncode Institute, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center, 3584 CT Utrecht, the Netherlands.
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 FBXW7 hotspot mutations in human colon organoids. Functionally, FBXW7 mutation reduces EGF dependency of organoid growth by ~10,000-fold. Combined transcriptomic and proteomic analyses revealed increased EGFR protein stability in FBXW7 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. FBXW7 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.
Insights
FBXW7 mutations in colon organoids reduce cancer cell growth dependency on EGF by stabilizing EGFR. This impacts sensitivity to EGFR-MAPK inhibitors, offering insights into colorectal cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- FBXW7 (F-box and leucine-rich repeat protein 5) is a tumor suppressor E3 ubiquitin ligase targeting proteins for proteasomal degradation.
- Mutations in FBXW7 are implicated in various human cancers, including colorectal cancer (CRC).
- Epidermal Growth Factor Receptor (EGFR) signaling is crucial for cell proliferation and is a key target in CRC therapy.
Purpose of the Study:
- To investigate the functional consequences of FBXW7 mutations on EGFR signaling and colorectal cancer organoid growth.
- To elucidate the molecular mechanisms by which FBXW7 mutations affect EGFR protein stability and cellular dependency on EGF.
- To assess the impact of FBXW7 mutations on the efficacy of EGFR-targeted therapies.
Main Methods:
- CRISPR base editing was employed to introduce specific FBXW7 hotspot mutations into human colon organoids.
- Transcriptomic and proteomic analyses were performed to assess changes in gene and protein expression and stability.
- EGFR phosphodegron motifs were investigated, including CRISPR-mediated disruption of the T693 phosphodegron.
- CRC-derived organoid lines and a patient cohort treated with panitumumab were used for validation.
Main Results:
- FBXW7 mutations drastically reduced EGF dependency in colon organoids (~10,000-fold).
- Mutant organoids exhibited increased EGFR protein stability due to impaired degradation.
- Disruption of the EGFR T693 phosphodegron mimicked FBXW7 mutation effects, reducing degradation and EGF dependency.
- FBXW7 mutant organoids and patient-derived tumors showed reduced sensitivity to EGFR-MAPK inhibitors like panitumumab.
Conclusions:
- FBXW7 mutations promote cancer cell survival by enhancing EGFR protein stability and reducing reliance on EGF signaling.
- Impaired EGFR turnover due to FBXW7 mutations confers resistance to EGFR-targeted therapies.
- Understanding FBXW7's role in EGFR regulation is critical for developing effective CRC treatment strategies.
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