Mutations in RAS or BRAF are associated with poor prognosis and resistance to epidermal growth factor receptor (EGFR)-targeted therapy in colorectal cancer (CRC). Despite their common ability to activate downstream genes such as MEK and ERK, the therapeutic benefit of MEK inhibitors for patients with RAS/BRAF mutant CRC is limited, highlighting the need for biomarkers to predict the efficacy of MEK inhibition. Previously, we reported that a change in phosphorylation of ribosomal protein S6 (pS6) after MEK inhibition was significantly associated with sensitivity to MEK inhibition in gastric cancer cells. Here, we investigated the value of the response in pS6 for predicting the efficacy of trametinib, a MEK inhibitor, in patients with RAS/BRAF mutant CRC using patient-derived CRC organoids. We found that a subset of CRC cell lines and organoids were sensitive to trametinib. The change in phosphorylated ERK, a downstream molecule of the RAS/RAF/MEK pathway, was not significantly associated with trametinib sensitivity. On the other hand, only those with sensitivity showed a reduction of pS6 levels in response to trametinib. The change in pS6 after trametinib treatment was detectable by Western blotting, immunohistochemistry or immunocytochemistry. We also demonstrated an impact of MEK inhibition on pS6 in vivo using a xenograft model. Our data suggest that, in combination with patient-derived organoids, immunostaining-based detection of pS6 could be useful for prediction of trametinib sensitivity.
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The data that support the findings of this study are available from the corresponding authors, upon reasonable request.
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We would like to thank Ms Mami Kimoto for their excellent assistance with experiments. We are also grateful to Hans Clevers, Tomohiro Mizutani, Else Driehuis and Stieneke van den Brink for critical advice on organoid experiments.
This work was supported at the Discretion of the President of Oita University (2019) and partly by JSPS KAKENHI Grant Number 18K15283.
Conflict of interest
The authors declare no competing interests.
This study was approved by the ethics committee of Oita University Faculty of Medicine (approval number: 1541).
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Hirashita, Y., Tsukamoto, Y., Kudo, Y. et al. Early response in phosphorylation of ribosomal protein S6 is associated with sensitivity to trametinib in colorectal cancer cells. Lab Invest (2021). https://doi.org/10.1038/s41374-021-00590-w