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Regulation of MEK inhibitor selumetinib sensitivity by AKT phosphorylation in the novel BRAF L525R mutant.
Nakai, Chikako; Mimaki, Sachiyo; Matsushima, Koutatsu; Shinozaki, Eiji; Yamazaki, Kentaro; Muro, Kei; Yamaguchi, Kensei; Nishina, Tomohiro; Yuki, Satoshi; Shitara, Kohei; Bando, Hideaki; Suzuki, Yutaka; Akagi, Kiwamu; Nomura, Shogo; Fujii, Satoshi; Sugiyama, Masaya; Nishida, Nao; Mizokami, Masashi; Koh, Yasuhiro; Koshizaka, Takuya; Okada, Hideki; Abe, Yukiko; Ohtsu, Atsushi; Yoshino, Takayuki; Tsuchihara, Katsuya.
Afiliação
  • Nakai C; Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
  • Mimaki S; G&G Science Co. Ltd., 4-1-1 Misato, Matsukawamachi, Fukushima, 960-1242, Japan.
  • Matsushima K; Division of Translational Informatics, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
  • Shinozaki E; G&G Science Co. Ltd., 4-1-1 Misato, Matsukawamachi, Fukushima, 960-1242, Japan.
  • Yamazaki K; Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-0063, Japan.
  • Muro K; Division of Gastrointestinal Oncology, Shizuoka Cancer Center, 1007 Shimo-Nagakubo, Nagaizumi-Cho, Sunto, Shizuoka, 411-8777, Japan.
  • Yamaguchi K; Department of Clinical Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan.
  • Nishina T; Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-0063, Japan.
  • Yuki S; Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, 160 Minamiumemotomachi, Matsuyama, Ehime, 791-0245, Japan.
  • Shitara K; Department of Gastroenterology and Hepatology, Hokkaido University Hospital, Sapporo, Japan.
  • Bando H; Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
  • Suzuki Y; Department of Clinical Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan.
  • Akagi K; Department of Computational Biology, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba, 277-8561, Japan.
  • Nomura S; Division of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, 818 Komuro, Inami-machi, Kitaadachi, Saitama, 362-0806, Japan.
  • Fujii S; Biostatistics Division, Center for Research and Administration and Support, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
  • Sugiyama M; Department of Molecular Pathology, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0004, Japan.
  • Nishida N; Genome Medical Sciences Project, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan.
  • Mizokami M; Genome Medical Sciences Project, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan.
  • Koh Y; Genome Medical Sciences Project, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba, 272-8516, Japan.
  • Koshizaka T; Third Department of Internal Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama, 641-8509, Japan.
  • Okada H; G&G Science Co. Ltd., 4-1-1 Misato, Matsukawamachi, Fukushima, 960-1242, Japan.
  • Abe Y; G&G Science Co. Ltd., 4-1-1 Misato, Matsukawamachi, Fukushima, 960-1242, Japan.
  • Ohtsu A; G&G Science Co. Ltd., 4-1-1 Misato, Matsukawamachi, Fukushima, 960-1242, Japan.
  • Yoshino T; National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
  • Tsuchihara K; Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
Int J Clin Oncol ; 28(5): 654-663, 2023 May.
Article em En | MEDLINE | ID: mdl-36856908
BACKGROUND: Oncogenic mutations in BRAF genes are found in approximately 5-10% of colorectal cancers. The majority of BRAF mutations are located within exons 11-15 of the catalytic kinase domains, with BRAF V600E accounting for more than 80% of the observed BRAF mutations. Sensitivity to BRAF- and mitogen-activated protein kinase (MEK) inhibitors varies depending on BRAF mutations and tumor cell types. Previously, we newly identified, BRAF L525R-mutation, in the activation segment of the kinase in colorectal cancer patient. Here, we characterized the function of the BRAF L525R mutation. METHODS: HEK293 cells harboring a BRAF mutation (V600E or L525R) were first characterized and then treated with cetuximab, dabrafenib, and selumetinib. Cell viability was measured using WST-1 assay and the expression of proteins involved in the extracellular signal-regulated kinase (ERK) and protein kinase B (AKT) signaling pathways was evaluated using western blot analysis. RESULTS: The MEK inhibitor selumetinib effectively inhibited cell proliferation and ERK phosphorylation in BRAF L525R cells but not in BRAF V600E cells. Further studies revealed that AKT phosphorylation was reduced by selumetinib in BRAF L525R cells but not in BRAF V600E cells or selumetinib-resistant BRAF L525R cells. Moreover, the AKT inhibitor overcame the selumetinib resistance. CONCLUSIONS: We established a model system harboring BRAF L525R using HEK293 cells. BRAF L525R constitutively activated ERK. AKT phosphorylation caused sensitivity and resistance to selumetinib. Our results suggest that a comprehensive network analysis may provide insights to identify effective therapies.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas Proto-Oncogênicas B-raf / Proteínas Proto-Oncogênicas c-akt Tipo de estudo: Diagnostic_studies Limite: Humans Idioma: En Revista: Int J Clin Oncol Assunto da revista: NEOPLASIAS Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Japão País de publicação: Japão

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas Proto-Oncogênicas B-raf / Proteínas Proto-Oncogênicas c-akt Tipo de estudo: Diagnostic_studies Limite: Humans Idioma: En Revista: Int J Clin Oncol Assunto da revista: NEOPLASIAS Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Japão País de publicação: Japão