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

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

来源：Cancer Letters, 2017, 384: 27-38.

DOI：10.1016/j.canlet.2016.10.015

• Breast cancer
• mTOR pathway
• DYRK2
• Everolimus

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.

• 出版日期2017-1-1