TAS-116 inhibits oncogenic KIT signalling on the Golgi in both imatinib-naïve and imatinib-resistant gastrointestinal stromal tumours

Abstract

BACKGROUND: Despite the effectiveness of imatinib mesylate (IM), most gastrointestinal stromal tumours (GISTs) develop IM resistance, mainly due to the additional kinase-domain mutations accompanied by concomitant reactivation of KIT tyrosine kinase. Heat-shock protein 90 (HSP90) is one of the chaperone molecules required for appropriate folding of proteins such as KIT. METHODS: We used a novel HSP90 inhibitor, TAS-116, which showed specific binding to HSP90α/β with low toxicity in animal models. The efficacy and mechanism of TAS-116 against IM-resistant GIST were evaluated by using IM-naïve and IM-resistant GIST cell lines. We also evaluated the effects of TAS-116 on the other HSP90 client protein, EGFR, by using lung cell lines. RESULTS: TAS-116 inhibited growth and induced apoptosis in both IM-naïve and IM-resistant GIST cell lines with KIT activation. We found KIT was activated mainly in intracellular compartments, such as trans-Golgi cisternae, and TAS-116 reduced autophosphorylated KIT in the Golgi apparatus. In IM-resistant GISTs in xenograft mouse models, TAS-116 caused tumour growth inhibition. We found that TAS-116 decreased phosphorylated EGFR levels and inhibited the growth of EGFR-mutated lung cancer cell lines. CONCLUSION: TAS-116 may be a novel promising drug to overcome tyrosine kinase inhibitor-resistance in both GIST and EGFRmutated lung cancer.

Non-Small-Cell Lung Cancer Signaling Pathways, Metabolism, and PD-1/PD-L1 Antibodies

“…P53RRA regulates metabolic genes, including SLC7A11 and TIGAR (p53-inducible regulator of glycolysis and apoptosis), promoting the accumulation of lipid ROS and intracellular iron, then inducing ferroptosis and apoptosis and cell cycle arrest in a p53-dependent manner [ 105 ]. A549 is a cell line that highly expresses P53RRA [ 105 ], however, this is in contradiction with the other study above mentioned where A549 displays high levels of SLC7A11 [ 101 ]. It was stated that P53RRA acts upstream of the p53 signaling pathway [ 105 ].…”

“…xCT (SLC7A11) is a cystine/glutamate antiporter that imports cystine into the cells, while exporting glutamate ( Figure 2 ). One molecule of cystine can then be converted into two molecules of cystine, a necessary step for glutathione (GSH) biosynthesis [ 39 , 40 , 101 ]. To quench reactive oxygen species (ROS), GSH is oxidized to GSH disulfide (GSSG), a reaction requiring nicotinamide adenine dinucleotide phosphate (NADPH).…”

“…Such mesenchymal therapy-resistant cells are dependent on the lipid hydroperoxidase GPX4 for survival [ 41 ] ( Figure 2 ). Sulfasalazine (SASP), a FDA-approved drug, has inhibitory effects on the function of xCT, by decreasing the supply of cystine [ 101 ]. xCT is overexpressed in NSCLC and correlates with worse survival.…”

“…xCT is highly expressed in different NSCLCs, such as A549, H520, and others, but not, for example, in H1869. Cell proliferation assays show dose-dependent growth induction induced by SASP in A549 and H520, but not in H1869.To maintain the intracellular glutamate pool, cells overexpressing xCT consume more glutamine for glutamate synthesis, a process of glutamine addiction [ 101 ]. Metabolic reprogramming by elevated glucose consumption, lactate production, and glutamine addiction, is a feature in NSCLC.…”

Heat Shock Proteins and PD-1/PD-L1 as Potential Therapeutic Targets in Myeloproliferative Neoplasms

“…Among the new HSP90 inhibitors, DN401 is a novel mitochondrial permeable pan-HSP90 inhibitor simultaneously targeting HSP90, GRP94, and TRAP1 DN401 [ 77 ]. Finally, TAS-116 is an HSP90-specific inhibitor that has shown encouraging results, with low toxicity in imatinib-mesylate-resistant gastrointestinal stromal tumors in mice, as well as in lung cancer cell lines [ 78 ].…”