title: Diminished DYRK2 sensitizes hormone receptor-positive breast cancer to everolimus by the escape from degrading mTOR.
abstract: Mammalian target of rapamycin (mTOR) inhibitor, everolimus, provides benefit for metastatic hormone receptor positive breast cancer after failure of the endocrine therapy. The present report highlights Dual Specificity Tyrosine Phosphorylation Regulated Kinase 2 (DYRK2) as a predictive marker for everolimus sensitivity. The key node and KEGG pathway analyses revealed that mTORC1 pathway is activated in DYRK2-depleted cells. Everolimus was more effective in DYRK2-depleted cells compared with control cells. In xenograft model, everolimus treatment significantly inhibited tumor growth compared with vehicle or eribulin treatment. In clinical analysis, patients with low DYRK2 expression acquired longer treatment period and had higher clinical benefit rate than those with high DYRK2 expression (171 vs 82 days; P < 0.05 and 50% vs 12.5%, respectively). We further investigated the underlying mechanism by which DYRK2 regulates mTORC1 pathway. The ectopic expression of DYRK2 promoted phosphorylation of Thr631 for the ubiquitination and degradation of mTOR. DYRK2 expression levels may thus predict clinical responses to everolimus.
authors.affiliation: Department of Biochemistry, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan; Department of Surgery, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
authors.forename: Rei
authors.initials: R
authors.lastname: Mimoto
authors.affiliation: Department of Biochemistry, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, USA.
authors.forename: Naoe T
authors.initials: NT
authors.lastname: Nihira
authors.affiliation: Department of Pathology, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Hirooka
authors.affiliation: Department of Surgery, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takeyama
authors.affiliation: Department of Biochemistry, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan. Electronic address: kyoshida@jikei.ac.jp.
authors.forename: Kiyotsugu
authors.initials: K
authors.lastname: Yoshida
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D000068338:Everolimus / Q000627:therapeutic use*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D000076222:Mechanistic Target of Rapamycin Complex 1; D008819:Mice, Nude; D046912:Multiprotein Complexes / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D054875:Ubiquitination; D023041:Xenograft Model Antitumor Assays; D000097603:Dyrk Kinases
chemical_list: D000970:Antineoplastic Agents; D000068338:Everolimus; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D046988:Proteasome Endopeptidase Complex; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; D000097603:Dyrk Kinases; C546842:MTOR protein, human
keywords: Breast cancer; DYRK2; Everolimus; mTOR pathway