title: SMK-17, a MEK1/2-specific inhibitor, selectively induces apoptosis in β-catenin-mutated tumors.
abstract: Although clinical studies have evaluated several MEK1/2 inhibitors, it is unlikely that MEK1/2 inhibitors will be studied clinically. BRAF mutations have been proposed as a responder marker of MEK1/2 inhibitors in a preclinical study. However, current clinical approaches focusing on BRAF mutations have shown only moderate sensitivity of MEK1/2 inhibitors. This has led to insufficient support for their promoted clinical adoption. Further characterization of tumors sensitive to MEK inhibitors holds great promise for optimizing drug therapy for patients with these tumors. Here, we report that β-catenin mutations accelerate apoptosis induced by MEK1/2 inhibitor. SMK-17, a selective MEK1/2 inhibitor, induced apoptosis in tumor cell lines harboring β-catenin mutations at its effective concentration. To confirm that β-catenin mutations and mutant β-catenin-mediated TCF7L2 (also known as TCF4) transcriptional activity is a predictive marker of MEK inhibitors, we evaluated the effects of dominant-negative TCF7L2 and of active, mutated β-catenin on apoptosis induced by MEK inhibitor. Indeed, dominant-negative TCF7L2 reduced apoptosis induced by MEK inhibitor, whereas active, mutated β-catenin accelerated it. Our findings show that β-catenin mutations are an important responder biomarker for MEK1/2 inhibitors.
authors: 1] Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Yokohama, Japan [2] Shinagawa R&D Center, Daiichi Sankyo Co. Ltd, Tokyo, Japan.
authors: Masaki
authors: M
authors: Kiga
authors: Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Yokohama, Japan.
authors: Ayako
authors: A
authors: Nakayama
authors: Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Yokohama, Japan.
authors: Yuki
authors: Y
authors: Shikata
authors: Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Yokohama, Japan.
authors: Yukiko
authors: Y
authors: Sasazawa
authors: Shinagawa R&D Center, Daiichi Sankyo Co. Ltd, Tokyo, Japan.
authors: Ryo
authors: R
authors: Murakami
authors: Shinagawa R&D Center, Daiichi Sankyo Co. Ltd, Tokyo, Japan.
authors: Toshiyuki
authors: T
authors: Nakanishi
authors: Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Yokohama, Japan.
authors: Etsu
authors: E
authors: Tashiro
authors: Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Yokohama, Japan.
authors: Masaya
authors: M
authors: Imoto
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002070:Butadienes / Q000633:toxicity; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004159:Diphenylamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy; D009570:Nitriles / Q000633:toxicity; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D002070:Butadienes; D009570:Nitriles; D047428:Protein Kinase Inhibitors; C572760:SMK-17; D013449:Sulfonamides; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; C113580:U 0126; D051176:beta Catenin; D004159:Diphenylamine; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2
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