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

Junya Iwasaki1,2, Toshiharu Komori1, Fumio Nakagawa1

  • 1Applied Pharmacology Section, Pharmacology Laboratory, Taiho Pharmaceutical Co., Ltd., Tokushima, Japan.

Anticancer Research
|July 3, 2019
PubMed
Abstract

Insights

Schlafen 11 (SLFN11) expression levels influence trabectedin

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Trabectedin is an approved DNA-damaging agent for advanced soft tissue sarcoma.
  • Schlafen 11 (SLFN11) is a key determinant of response to DNA-damaging agents.

Purpose of the Study:

  • To investigate the association between SLFN11 expression and trabectedin's antitumor activity.
  • To explore combination therapy with ATR inhibitors.

Main Methods:

  • Evaluated trabectedin's antitumor activity in cell lines with varying SLFN11 expression (RNA interference, CRISPR-Cas9).
  • Assessed combination therapy of ATR inhibitor and trabectedin in vitro and in vivo xenograft models.

Main Results:

  • SLFN11 knockdown reduced sensitivity to trabectedin.
  • ATR inhibitor enhanced trabectedin's activity in SLFN11-low/knockout models.

Conclusions:

  • SLFN11 expression is a critical factor in trabectedin's efficacy.
  • Combination with ATR inhibitors may overcome resistance.
Keywords:
DNA repairSchlafen11anticancer drugsarcomatrabectedin

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