論文

査読有り 国際誌
2020年12月17日

Inhibition of Akt/mTOR pathway overcomes intrinsic resistance to dasatinib in triple-negative breast cancer.

Biochemical and biophysical research communications
  • Yuya Haga
  • ,
  • Kazuma Higashisaka
  • ,
  • Lili Yang
  • ,
  • Naoki Sekine
  • ,
  • Ying Lin
  • ,
  • Hirofumi Tsujino
  • ,
  • Kazuya Nagano
  • ,
  • Yasuo Tsutsumi

533
4
開始ページ
672
終了ページ
678
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1016/j.bbrc.2020.09.143

Currently, the only therapeutic choice for the treatment of triple-negative breast cancer (TNBC) is chemotherapy. In TNBC, despite strong preclinical data, clinical trials of molecular targeted drugs, such as the Src tyrosine kinase inhibitor dasatinib, have failed because of the heterogeneity of TNBC cells. Here, we examined the mechanism of intrinsic resistance to dasatinib in five TNBC cell lines. First, we divided the TNBC cell lines into those sensitive or resistant to dasatinib and found that activation of Src was inhibited in all of the cell lines. In contrast, we found that dasatinib inhibited Akt phosphorylation in only the dasatinib-sensitive cell lines. Consequently, we found that combination treatment with dasatinib and an inhibitor of Akt or mTOR suppressed cell proliferation more than did either monotherapy in the dasatinib-resistant cell lines. Finally, to mimic intrinsic resistance, we established a dasatinib-tolerant TNBC cell line. In this cell line, the combinational effect of Akt/mTOR inhibition with dasatinib was observed, as it was in the cell lines with intrinsic resistance. Together, the present results show that the effect of dasatinib in TNBC is independent of Src inhibition, and that Akt/mTOR inhibition might be an effective strategy to overcome TNBC cells with intrinsic dasatinib resistance.

リンク情報
DOI
https://doi.org/10.1016/j.bbrc.2020.09.143
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/33036754
ID情報
  • DOI : 10.1016/j.bbrc.2020.09.143
  • PubMed ID : 33036754

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