Abstract
The aberrant activation of RAS/RAF/MEK/ERK signaling is important for KIT mutation-mediated tumorigenesis of gastrointestinal stromal tumor (GIST). In this study, we found that inhibition of RAF1 suppresses the activation of both wild-type KIT and primary KIT mutations in GIST, with primary KIT mutations showing greater sensitivity. This suggests a positive feedback loop between KIT and RAF1, wherein RAF1 facilitates KIT signaling. We further demonstrated that RAF1 associates with KIT and the kinase activity of RAF1 is necessary for its contribution to KIT activation. Accordingly, inhibition of RAF1 suppressed cell survival, proliferation, and cell cycle progression in vitro mediated by both wild-type KIT and primary KIT mutations. Inhibition of RAF1 in vivo suppressed GIST growth in a transgenic mouse model carrying germline KIT/V558A mutation, showing a similar treatment efficiency as imatinib, the first-line targeted therapeutic drug of GIST, while the combination use of imatinib and RAF1 inhibitor further suppressed tumor growth. Acquisition of drug-resistant secondary mutation of KIT is a major cause of treatment failure of GIST following targeted therapy. Like wild-type KIT and primary KIT mutations, inhibition of RAF1 suppressed the activation of secondary KIT mutation, and the cell survival, proliferation, cell cycle progression in vitro, and tumor growth in vivo mediated by secondary KIT mutation. However, the activation of secondary KIT mutation is less dependent on RAF1 compared with that of primary KIT mutations. Taken together, our results revealed that RAF1 facilitates KIT signaling and KIT mutation-mediated tumorigenesis of GIST, providing a rationale for further investigation into the use of RAF1 inhibitors alone or in combination with KIT inhibitor in the treatment of GIST, particularly in cases resistant to KIT inhibitors.
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Data reported in this paper are available from the corresponding author upon reasonable request.
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Acknowledgements
This study was supported by the National Natural Science Foundation of China (82373141, 82160521), the Natural Science Foundation of Ningxia province (2023AAC05060, 2023AAC03666), and the General Research Fund of the Research Grants Council of Hong Kong (14112618, 14119120).
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LZ conducted cell experiments, mouse experiments, and analyzed the data; ShZ, XC, JSh, SiZ, JT, KX, MW, CW contributed to molecular and cell biology experiments; JL, LZ and YY contributed to the data analysis and visualization; JSu conceptualized the project, JSu, SL and HZ designed and supervised the study; JSu and LZ drafted the manuscript. JSu, SL, HZ revised the manuscript. All authors read and approved the manuscript.
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Zhang, L., Zhang, S., Cao, X. et al. RAF1 facilitates KIT signaling and serves as a potential treatment target for gastrointestinal stromal tumor. Oncogene (2024). https://doi.org/10.1038/s41388-024-03063-8
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DOI: https://doi.org/10.1038/s41388-024-03063-8