1. Academic Validation
  2. Brexpiprazole Reduces Survivin and Reverses EGFR Tyrosine Kinase Inhibitor Resistance in Lung and Pancreatic Cancer

Brexpiprazole Reduces Survivin and Reverses EGFR Tyrosine Kinase Inhibitor Resistance in Lung and Pancreatic Cancer

  • Anticancer Res. 2019 Sep;39(9):4817-4828. doi: 10.21873/anticanres.13667.
Tomomi Sanomachi 1 2 Shuhei Suzuki 1 2 Keita Togashi 1 3 Shizuka Seino 1 Takashi Yoshioka 2 Chifumi Kitanaka 1 4 Masashi Okada 1 Masahiro Yamamoto 5
Affiliations

Affiliations

  • 1 Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata, Japan.
  • 2 Department of Clinical Oncology, Yamagata University School of Medicine, Yamagata, Japan.
  • 3 Department of Ophthalmology and Visual Sciences, Yamagata University School of Medicine, Yamagata, Japan.
  • 4 Research Institute for Promotion of Medical Sciences, Yamagata University Faculty of Medicine, Yamagata, Japan.
  • 5 Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata, Japan masahiro@med.id.yamagata-u.ac.jp.
Abstract

Background/aim: Although epidermal growth factor receptor (EGFR) is frequently activated in lung and pancreatic cancers, the efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs) is limited. Recently, brexpiprazole, an antipsychotic drug, was reported to chemosensitize glioma cells to osimertinib, a third-generation EGFR-TKI, by suppressing Survivin, an anti-apoptotic protein, but their combinational effects on lung and pancreatic cancers remain unknown. The aim of this study was to examine the combinational effects of brexpiprazole and osimertinib on lung and pancreatic Cancer cells in vitro and in vivo.

Materials and methods: YM155, a suppressor of Survivin, siRNA, and immunoblot were used to examine the role of Survivin in osimertinib-resistance. The effect of drugs on cell viability in vitro was examined by trypan blue staining. The in vivo effects of drugs on tumor growth were examined using a xenograft mouse model.

Results: Brexpiprazole exerted combinational effects with osimertinib in vitro. Pharmacological and genetic suppression of Survivin chemosensitized the cells to osimertinib. Moreover, the combination of brexpiprazole and osimertinib effectively suppressed tumor growth in a mouse xenograft model.

Conclusion: Brexpiprazole is a promising drug for lung and pancreatic Cancer in combination with osimertinib.

Keywords

Brexpiprazole; non-small cell lung cancer; osimertinib; pancreatic cancer; survivin.

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