Abstract
Approximately 40 families with multiple gastrointestinal stromal tumors (GISTs) and germline c-kit gene mutations have been reported. Three knock-in mouse models have been generated, and all the models showed a cecal GIST. In the present study, we established a cell line derived from cecal GIST in a familial GIST model mouse with KIT-Asp818Tyr. Since the established cells showed spindle-shaped morphology with atypical nuclei, and since immunohistochemistry revealed that they were positive for α-SMA but negative for KIT, CD34 and desmin, the phenotypes of the cells were reminiscent of dedifferentiated GIST-like ones but not the usual GIST-like ones. Gene expression analysis showed that the cell line, designated as DeGISTL1 cell, did not express c-kit gene apparently, but highly expressed HSP90 families and glutaminase 1. Pathway analysis of the cells revealed that metabolic pathway might promote their survival and growth. Pimitespib, a heat shock protein 90α/β inhibitor, and Telaglenastat, a selective glutaminase 1 inhibitor, inhibited proliferation of DeGISTL1 cells and the combination of these showed an additive effect. DeGISTL1 cells might be a good model of dedifferentiated GISTs, and combination of Pimitespib and Telaglenastat could be a possible candidate for treatment strategy for them.