Fig. 5

Proposed mechanisms of action of olverembatinib in SDH-deficient GIST. Red arrows represent upregulation in the SDH-deficient GIST cells. The purple dotted lines with a bar represent inhibition by olverembatinib. Increased lipid uptake, lipid synthesis, and FABP, FATP and CD36 protein expression are found in SDH-deficient GIST tumor cells, and olverembatinib treatment dose-dependently suppressed lipid uptake, CD36, and proteins involved in the regulation of lipid metabolism. The accumulation of cellular succinate due to SDH deficiency leads to the inhibition of prolyl hydroxylases (PHDs), which in turn results in hypoxia-inducible factor (HIF) stabilization and HIF activation. Activated HIF1α/2α induces the expression of genes responsible for FA uptake and triacylglycerol (TAG) synthesis. Consequently, lipid enrichment in SDH-deficient GIST tumor cells may provide a major energy source for cell proliferation and metastasis. Moreover, stabilized HIF1α upregulates the expression of genes, such as Glut1, IGF, TGFα, and VEGF, that are involved in angiogenesis; glucose metabolism; and cell proliferation, survival, invasion, and metastasis. The results reported in this study demonstrated that olverembatinib blocks the energy source of SDH-deficient tumor cells by suppressing lipid uptake as well as lipid metabolism, which has not been previously reported with other TKIs used for the treatment of SDH-deficient cancers. In addition, olverembatinib inhibits other signaling pathways, including the VEGFR, IGF1R, FGFR, and SRC pathways, which have been implicated in the tumorigenesis of SDH-deficient neoplasms. Taken together, these findings indicate that olverembatinib exerts antitumor effects by regulating lipid uptake, lipid metabolism, and multiple tumorigenic pathways involved in proliferation, angiogenesis, apoptosis, and survival. Created in BioRender. Yang, C. (2025) https://BioRender.com/to2gqhf (agreement number: VO28QGKQUY)