Newly discovered link between FBXW7 mutations and EGFR signaling in colorectal cancer

The Organoid group at the Hubrecht Institute have identified a new link between FBXW7 mutations and EGFR signaling activity. The FBXW7 gene is commonly mutated in colorectal cancer and such mutations have been associated with worse treatment outcome. The researchers used colon organoids and the CRISPR/Cas9 gene editing technique to investigate the consequences of multiple common FBXW7 mutations. Further understanding of the link with EGFR signaling could help improve treatment strategies for colorectal cancer. The research was published on March 14th in Proceedings of the national academies of sciences (PNAS).

Cancer is caused by the accumulation of mutations in different genes. One commonly mutated gene is the FBXW7 gene which normally plays an important role in the protein degradation system. Although the mutation has been identified in many different types of cancer, it is most often seen in colorectal and endometrial cancer. For cancer in the colon, FBXW7 mutations are involved in 10% of patients and result in worse treatment outcome. However, the FBXW7 mutation is not yet well understood and the reason for the poor treatment outcome is currently unknown. “Therefore, we set out to completely understand the impact of these mutations, hopefully giving us a better idea of how we can treat affected patients,” says Matteo Boretto one of the leading researchers on the project.

Introducing mutations into organoids

To investigate the FBXW7 mutations the researchers used organoids which work as miniature organs that can be cultured in the laboratory. Maarten Geurts one of the leading researchers on the project explains: “We used healthy colon organoids, or mini-intestines as they closely recapitulate the organs in our body and therefore allow us to study health and disease in great detail”. The FBXW7 mutations were introduced through the CRISPR/Cas9 base editing technique. This technique enables the researchers to make specific mutations in the gene by changing the DNA code. Seven different FBXW7 mutations were introduced in the organoids, which constitute the most commonly occurring mutations in the gene.

New link with the EGFR signaling pathway

Mutations leading to colon cancer affect a wide range of signaling pathways, these consist of chains of molecules, which send messages to each other in order to activate or stop processes. One pathway that is affected by cancer is the epidermal growth factor receptor (EGFR) pathway. As this signaling chain is usually overactivated in cancer, treatment options often include EGFR inhibitors. The researchers found that FBXW7 mutations lead to increased signaling activity of the EGFR pathway and a decreased response to anti-EGFR treatment. Boretto says: “The FBXW7 gene normally plays an important role in degradation pathways by putting a small flag on the EGFR, signaling for its degradation. We hypothesize based on our data that the mutated form could no longer do so”. Without the flag, EGFR is not degraded and therefore it remains active rendering EGFR inhibitors less effective. Boretto continues: “This link between EGFR signaling and FBXW7 mutations had not been shown before.”

Improving treatment options for patients

The link between EGFR signaling and FBXW7 mutations is important to investigate in order to improve treatment options for colorectal cancer. Currently, many patients are treated with EGFR inhibitors in lack of a better option. However, since the researchers found that this treatment option is less effective for patients with the mutation who were affected by metastatic colorectal cancer it is important to fully understand this link.

Publication

EGFR is a target of the tumor-suppressor E3 ligase FBXW. 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 and Hans Clevers. PNAS, 2024.

* These authors contributed equally.

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About Hans Clevers:

Hans Clevers is advisor/guest researcher at the Hubrecht Institute for Developmental Biology and Stem Cell Research (KNAW) and at the Princess Máxima Center for Pediatric Oncology. He holds a professorship in Molecular Genetics from the Utrecht University and is an Oncode Investigator. Hans Clevers has been the Head of Pharma Research and Early Development (pRED) at Roche since 2022. He previously held directorship/President positions at the Hubrecht Institute, the Royal Netherlands Academy of Arts and Sciences and the Princess Máxima Center for pediatric oncology.

About the Hubrecht Institute:

The Hubrecht Institute is a research institute focused on developmental and stem cell biology. Because of the dynamic character of the research, the institute has a variable number of research groups, around 20, that do fundamental, multidisciplinary research on healthy and diseased cells, tissues and organisms. The Hubrecht Institute is a research institute of the Royal Netherlands Academy of Arts and Sciences (KNAW), situated on Utrecht Science Park. Since 2008, the institute is affiliated with the UMC Utrecht, advancing the translation of research to the clinic. The Hubrecht Institute has a partnership with the European Molecular Biology Laboratory (EMBL). For more information, visit www.hubrecht.eu.