Epidermal growth factor receptor (EGFR) is a target of the tumor-suppressor E3 ligase FBXW7

Epidermal growth factor receptor (EGFR) is a target of the tumor-suppressor E3 ligase FBXW7

Proceedings of the National Academy of Sciences

10.1073/pnas.2309902121

http://dx.doi.org/10.1073/pnas.2309902121

Matteo Boretto, Maarten H. Geurts, Shashank Gandhi, Ziliang Ma, Nadzeya Staliarova, Martina Celotti, Sangho Lim, Gui-Wei He, Rosemary Millen, Else Driehuis, Harry Begthel, Lidwien Smabers, Jeanine Roodhart, Johan van Es, Wei Wu, Hans Clevers

14 March 2024

Boretto, M., Geurts, M. H., Gandhi, S., Ma, Z., Staliarova, N., Celotti, M., Lim, S., He, G.-W., Millen, R., Driehuis, E., Begthel, H., Smabers, L., Roodhart, J., van Es, J., Wu, W., & Clevers, H. (2024). Epidermal growth factor receptor (EGFR) is a target of the tumor-suppressor E3 ligase FBXW7. Proceedings of the National Academy of Sciences, 121(12). https://doi.org/10.1073/pnas.2309902121

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.

Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)

This work was supported by an award from the Cancer Research UK Grand Challenge (C6307/A29058) and the Mark Foundation for Cancer Research to the SPECIFICANCER team and by the Netherlands Organ-on-Chip Initiative, an NWO Gravitation project (024.003.001) funded by the Ministry of Education, Culture and Science of the government of the Netherlands.

https://oar.a-star.edu.sg/communities-collections/articles/19879

1091-6490
0027-8424

Singapore Immunology Network