Diminished DYRK2 sensitizes hormone receptor-positive breast cancer to everolimus by the escape from degrading mTOR

Rei Mimoto; Naoe T Nihira; Shinichi Hirooka; Hiroshi Takeyama; Kiyotsugu Yoshida

doi:10.1016/j.canlet.2016.10.015

Diminished DYRK2 sensitizes hormone receptor-positive breast cancer to everolimus by the escape from degrading mTOR

Cancer Lett. 2017 Jan 1:384:27-38. doi: 10.1016/j.canlet.2016.10.015. Epub 2016 Oct 13.

Authors

Rei Mimoto¹, Naoe T Nihira², Shinichi Hirooka³, Hiroshi Takeyama⁴, Kiyotsugu Yoshida⁵

Affiliations

¹ 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.
² 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.
³ Department of Pathology, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
⁴ Department of Surgery, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan.
⁵ Department of Biochemistry, Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan. Electronic address: [email protected].

PMID: 27746162
DOI: 10.1016/j.canlet.2016.10.015

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.

Keywords: Breast cancer; DYRK2; Everolimus; mTOR pathway.

MeSH terms

Animals
Antineoplastic Agents / therapeutic use*
Breast Neoplasms / drug therapy*
Breast Neoplasms / enzymology
Breast Neoplasms / pathology
Dose-Response Relationship, Drug
Down-Regulation
Dyrk Kinases
Everolimus / therapeutic use*
Female
Gene Expression Regulation, Neoplastic
Humans
MCF-7 Cells
Mechanistic Target of Rapamycin Complex 1
Mice, Nude
Multiprotein Complexes / metabolism
Mutation
Phosphorylation
Proteasome Endopeptidase Complex / metabolism
Protein Kinase Inhibitors / therapeutic use*
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism*
Protein-Tyrosine Kinases / genetics
Protein-Tyrosine Kinases / metabolism*
Proteolysis
RNA Interference
Signal Transduction / drug effects
TOR Serine-Threonine Kinases / antagonists & inhibitors*
TOR Serine-Threonine Kinases / genetics
TOR Serine-Threonine Kinases / metabolism
Time Factors
Transfection
Tumor Burden / drug effects
Ubiquitination
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Multiprotein Complexes
Protein Kinase Inhibitors
Everolimus
MTOR protein, human
Protein-Tyrosine Kinases
Mechanistic Target of Rapamycin Complex 1
Protein Serine-Threonine Kinases
TOR Serine-Threonine Kinases
Proteasome Endopeptidase Complex