BPR1J373, a novel multitargeted kinase inhibitor, effectively suppresses the growth of gastrointestinal stromal tumor

Hui Jen Tsai*, Weir Torn Jiaang, Neng Yao Shih, Jonathan A. Fletcher, Ming Jon Lin, Ming Yu Yang, Chiung Tong Chen, Tsu An John Hsu, Chun Chieh Wu, Hui You Lin, Li Tzong Chen

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

4 Scopus citations

Abstract

Gastrointestinal stromal tumor (GIST) is a type of KIT-driven cancer. KIT gene mutations are found in approximately 80% of GISTs, and most of these mutations occur in exon 9 and exon 11. Imatinib has been successfully used as a first-line treatment for advanced GIST, with a significant improvement in progression-free survival (PFS) and overall survival. However, disease progression might develop due to primary or secondary resistance to imatinib. Sunitinib and regorafenib have been approved as second- and third-line treatments for advanced GIST patients, with median PFS values of 6.8 and 4.8 months, respectively. However, these relatively modest improvements in PFS underscore the need for more effective KIT inhibitors. BPR1J373 is a multitargeted kinase inhibitor that has been shown to inhibit the proliferation of KIT-driven acute myeloid leukemia cells in vitro and in vivo. In this study, we found that BPR1J373 inhibited proliferation and induced apoptosis by targeting KIT in GIST cells with KIT gene mutations. BPR1J373 also induced cell cycle arrest and senescent change in KIT-mutant GIST48 cells, probably by targeting aurora kinase A. In the KIT-null COS-1 cell-based system, BPR1J373 effectively inhibited KIT with single or double mutations of KIT developed in GIST. The antiproliferative effect was also consistently evident in GIST430 tumor-grafted mice. The results suggest that BPR1J373 could be a potential anticancer drug for GIST and deserves further investigation for clinical applications.

Original languageEnglish
Pages (from-to)3591-3601
Number of pages11
JournalCancer Science
Volume109
Issue number11
DOIs
StatePublished - 11 2018

Bibliographical note

Publisher Copyright:
© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Keywords

  • Aurora kinase A
  • BPR1J373
  • KIT
  • gastrointestinal stromal tumor
  • multitargeted kinase inhibitor

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