Schlafen11 Expression Is Associated With the Antitumor Activity of Trabectedin in Human Sarcoma Cell Lines

  • Anticancer Res. 2019 Jul;39(7):3553-3563. doi: 10.21873/anticanres.13501.
Junya Iwasaki  1  2 ,  Toshiharu Komori  1 ,  Fumio Nakagawa  1 ,  Hideki Nagase  1 ,  Junji Uchida  1 ,  Kenichi Matsuo  3 ,  Yoshihiro Uto  4
Affiliations
  • 1. Applied Pharmacology Section, Pharmacology Laboratory, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan.
  • 2. Graduate School of Technology, Industrial and Social Sciences, Tokushima University, Tokushima, Japan.
  • 3. Pharmacology Laboratory, Taiho Pharmaceutical Co., Ltd., Tsukuba, Japan.
  • 4. Graduate School of Technology, Industrial and Social Sciences, Tokushima University, Tokushima, Japan [email protected].
PMID: 31262879 DOI: 10.21873/anticanres.13501
Abstract

Background/aim: Trabectedin is a DNA-damaging agent and has been approved for the treatment of patients with advanced soft tissue sarcoma. Schlafen 11 (SLFN11) was identified as a dominant determinant of the response to DNA-damaging agents. The aim of the study was to clarify the association between SLFN11 expression and the antitumor activity of trabectedin.

Materials and methods: The antitumor activity of trabectedin was evaluated under different expression levels of SLFN11 regulated by RNA interference and CRISPR-Cas9 systems, and the combined antitumor activity of ataxia telangiectasia and Rad3-related protein kinase (ATR) inhibitor and trabectedin in sarcoma cell lines using in vitro a cell viability assay and in vivo xenograft models.

Results: SLFN11-knockdown cell lines had a lower sensitivity to trabectedin, compared to parental cells. ATR Inhibitor enhanced the antitumor activity of trabectedin in SLFN11-knockdown cells and in a SLFN11-knockout xenograft model.

Conclusion: SLFN11 expression might be a key factor in the antitumor activity of trabectedin.

Keywords
DNA repair; Schlafen11; anticancer drug; sarcoma; trabectedin.
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