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    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. © 2021. The Author(s), under exclusive licence to United States and Canadian Academy of Pathology.

    Citation

    Yuka Hirashita, Yoshiyuki Tsukamoto, Yoko Kudo, Daisuke Kakisako, Shusaku Kurogi, Naoki Hijiya, Chisato Nakada, Tomohisa Uchida, Teijiro Hirashita, Takahiro Hiratsuka, Tomonori Akagi, Yoshitake Ueda, Hidefumi Shiroshita, Tsuyoshi Etoh, Kazuhiro Mizukami, Koichi Honda, Tadayoshi Okimoto, Masaaki Kodama, Masafumi Inomata, Masatsugu Moriyama, Kazunari Murakami. Early response in phosphorylation of ribosomal protein S6 is associated with sensitivity to trametinib in colorectal cancer cells. Laboratory investigation; a journal of technical methods and pathology. 2021 Aug;101(8):1036-1047

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    PMID: 33911189

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