RAF1 contributes to cell proliferation and STAT3 activation in colorectal cancer independently of microsatellite and KRAS status

Autor(en)

Coralie Dorard, Claire Madry, Olivier Buhard, Stefanie Toifl, Sebastian Didusch, Toky Ratovomanana, Quentin Letourneur, Helmut Dolznig, Mathew J. Garnett, Alex Duval, Manuela Baccarini

Abstrakt

More than 30% of all human cancers are driven by RAS mutations and activating KRAS mutations are present in 40% of colorectal cancer (CRC) in the two main CRC subgroups, MSS (Microsatellite Stable) and MSI (Microsatellite Instable). Studies in RAS-driven tumors have shown essential roles of the RAS effectors RAF and specifically of RAF1, which can be dependent or independent of RAF’s ability to activate the MEK/ERK module. In this study, we demonstrate that RAF1, but not its kinase activity, plays a crucial role in the proliferation of both MSI and MSS CRC cell line-derived spheroids and patient-derived organoids, and independently of KRAS mutation status. Moreover, we could define a RAF1 transcriptomic signature which includes genes that contribute to STAT3 activation, and could demonstrate that RAF1 ablation decreases STAT3 phosphorylation in all CRC spheroids tested. The genes involved in STAT3 activation as well as STAT3 targets promoting angiogenesis were also downregulated in human primary tumors expressing low levels of RAF1. These results indicate that RAF1 could be an attractive therapeutic target in both MSI and MSS CRC regardless of their KRAS status and support the development of selective RAF1 degraders rather than RAF1 inhibitors for clinical use in combination therapies.

Organisation(en)

Department für Mikrobiologie, Immunbiologie und Genetik, Max Perutz Labs

Externe Organisation(en)

Medizinische Universität Wien, Wellcome Trust Sanger Institute, Université Paris VI - Pierre-et-Marie-Curie

Journal

Oncogene

Band

42

Seiten

1649-1660

Anzahl der Seiten

12

ISSN

0950-9232

DOI

https://doi.org/10.1038/s41388-023-02683-w

Publikationsdatum

05-2023

Peer-reviewed

Ja

ÖFOS 2012

106023 Molekularbiologie, 106052 Zellbiologie

ASJC Scopus Sachgebiete

Molecular Biology, Genetics, Cancer Research

Sustainable Development Goals

SDG 3 – Gesundheit und Wohlergehen

Link zum Portal

https://ucrisportal.univie.ac.at/de/publications/raf1-contributes-to-cell-proliferation-and-stat3-activation-in-colorectal-cancer-independently-of-microsatellite-and-kras-status(6ce17750-6d21-43da-bb55-b41f061766ca).html