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

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.

• Authors: Tomomi Sanomachi, Shuhei Suzuki, Keita Togashi, Shizuka Seino, Takashi Yoshioka, Chifumi Kitanaka, Masashi Okada, Masahiro Yamamoto
• Journal: Anticancer research (Anticancer Res) Vol. 39 Issue 9 Pg. 4817-4828 (Sep 2019) ISSN: 1791-7530 [Electronic] Greece
• PMID: 31519584 (Publication Type: Journal Article)
• Copyright: Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Chemical References

• Acrylamides
• Aniline Compounds
• Protein Kinase Inhibitors
• Quinolones
• RNA, Small Interfering
• Survivin
• Thiophenes
• brexpiprazole
• osimertinib
• EGFR protein, human
• ErbB Receptors

Topics

• Acrylamides (pharmacology)
• Aniline Compounds (pharmacology)
• Animals
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Disease Models, Animal
• Drug Resistance, Neoplasm (genetics)
• ErbB Receptors (antagonists & inhibitors)
• Humans
• Male
• Mice
• Neoplastic Stem Cells (drug effects, metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Quinolones (pharmacology)
• RNA, Small Interfering (genetics)
• Survivin (genetics)
• Thiophenes (pharmacology)
• Xenograft Model Antitumor Assays