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

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.

Molecular Comparison of Imatinib-Naïve and Resistant Gastrointestinal Stromal Tumors: Differentially Expressed microRNAs and mRNAs

“…These genes are found upregulated in many cancers and targeted inhibitors have been developed [36]. In GIST AURKA expression has been identified as a negative prognostic factor [37,38] and has recently been implicated as a therapeutic target [39]. The significance of FOXM1 in GIST was recently emphasized by reporting its role in GIST progression [40].…”

Mitochondrial phosphoenolpyruvate carboxykinase promotes tumor growth in estrogen receptor‐positive breast cancer via regulation of the mTOR pathway

“…The experiment to compare cell cycle transitions in MCF‐7 cells treated with different concentrations of 3‐MP at different time points were performed in quadruplicate. The details of cell processing and flow cytometric analysis of the cell cycle were as described in our previous paper, 22 and the data were analyzed by using ModFit LT 2.0 (Becton Dickinson).…”