PMCID
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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SR1, another anti-KIT antibody, inhibited GIST 882 cells (IC50: 70 nM) but had much less efficacy against imatinib-resistant GIST 48 and GIST 430 cells (IC50 > 5 µM).
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Although SR1 inhibited the proliferation of GIST cells in mouse models , the GIST tumors located in the peritoneal cavity and the antibody was injected intraperitoneally.
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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This may explain the better in vivo efficacy of SR1 compared to CK6 .
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Clinical trials (NCT02452424, NCT01316263) evaluating antibody targeting (CSF1R + PD-1, PDGFRAα) in patients with advanced GIST were terminated due to limited efficacy or poor accrual.
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Overall, therapeutic antibody therapy has limited efficacy in preclinical and clinical settings.
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Antibody drug conjugate (ADC) is another drug candidate for primary and advanced GISTs.
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Antibodies confer specificity for highly toxic chemotherapeutic drugs, such as mertasine and camptothecin (Fig. 3D).
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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ADCs targeting KIT (LOP628 and NN2101-DM1) have demonstrated strong inhibitory effects at sub-nanomolar concentrations against both imatinib-sensitive and -insensitive GIST cells (GIST T1 and GIST 430/654) both in vitro and in vivo [89, 90].
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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DS-6157a, an ADC targeting GPR20, exhibited GPR20-expression-dependent antitumor activity in GIST xenograft models, but its preclinical potency was less than that of ADCs targeting KIT .
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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In a clinical trial evaluating the efficacy of DS-6157a on advanced GIST (34 patients available for analysis, NCT04276415), the maximum tolerated dose (MTD) was 6.4 mg/kg, 18 patients (53%) experienced stable disease, mPFS across all dose levels was 3.6 months, no objective responses existed in patients with KIT-mutant GIST.
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Tumor shrinkage was observed in all 4 patients with wild-type KIT GIST treated at different doses.
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Although this trial was terminated, it provides potential of ADC for the treatment of GIST with wild-type KIT .
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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CAR T therapy is another powerful method to combat cancer.
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Currently, only SCF has been reported as a targeting domain for CAR T therapy in GISTs, showing efficacy in animal models .
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Oncoproteins regulate key enzymes in metabolic pathways, providing energy and materials essential for cell proliferation through mechanisms involving AKT kinase and the transcription factor c-MYC [94–96].
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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In cancer cells, crucial metabolic processes include the uptake and utilization of amino acids and glucose, as well as the biosynthesis of carbohydrates, polysaccharides, proteins, lipids, and nucleic acids.
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Targeting critical enzymes in these metabolic pathways—such as those involved in glucose metabolism, glutamine metabolism, fatty acid synthesis, and nucleotide synthesis—holds promise .
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Changes in the metabolism of GIST cells were assessed based on the presence or absence of TKIs treatment and their sensitivity to TKI therapy.
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Glycolysis is a key feature of altered metabolism in cancer and presents as a potential therapeutic target.
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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In a study of GIST patient samples, glucose uptake mediated by glucose transporter 1 (GLUT1) and glycolysis activity involving hexokinase-1 (HK1), lactate dehydrogenase A (LDHA), and pyruvate kinase isozyme M2 (PKM2) were found to be upregulated in high-risk tumors compared to low-risk tumors .
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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In GIST T1 (IC50 10.7 nM) and GIST 882 (IC50 17.8 nM) cells, treatment with imatinib for 2 years resulted in T1R (IC50 46 µM) and 882R (IC50 55 µM) cells without secondary mutations, which show elevated glycolysis, increased lactate production (ECAR), and a lower oxygen consumption rate (OCR) .
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Another study reported that 882R (IC50 5 µM) cells exhibited higher glucose uptake, increased expression of LDHA and oxidative phosphorylation (OXPHOS) protein compared with GIST 882 cells.
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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HK inhibitor (3-bromopyruvate) and LDHA inhibitor gossypol effectively inhibited glycolysis, reduced cell viability and induced apoptosis .
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Glucose mimic 2-deoxyglucose (2DG) inhibits HK activity, thereby disrupting glycolysis.
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Although 2DG (IC50 0.5–2.5 µM) inhibited the proliferation of imatinib-resistant GIST cells in vitro, it had limited inhibitory effects in vivo, possibly due to insufficient drug concentration .
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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In addition to glycolysis, other glucose-related metabolic pathways have also been reported in GIST.
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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A preliminary study using transcriptome and metabolome analysis, comparing GIST tissue with adjacent normal tissue revealed that galactose metabolism was involved in GIST malignant progression via aldose reductase .
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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The pentose phosphate pathway (PPP) generates NADPH and ribulose 5-phosphate from glucose, with ribulose 5-phosphate being the precursor for nucleotide synthesis.
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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6-Phosphogluconate dehydrogenase (PGD) catalyzes the conversion of 6-phosphogluconate to ribulose 5-phosphate, and was upregulated in imatinib-resistant GIST cells (Fig. 4A).Fig.
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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4Metabolism changes in GISTs.
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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A. Metabolic changes in GISTs without imatinib treatment.
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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B. Metabolic changes in GISTs under insufficient concentrations of imatinib.
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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C. Metabolic changes in GISTs with sufficient concentrations of imatinib.
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Metabolism changes in GISTs.
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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A. Metabolic changes in GISTs without imatinib treatment.
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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B. Metabolic changes in GISTs under insufficient concentrations of imatinib.
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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C. Metabolic changes in GISTs with sufficient concentrations of imatinib.
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Lipids play essential roles in tumor cells as they are building blocks of cell membranes, an energy source, and participate in cell signaling .
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Metabolite analysis of blood samples from GIST patients revealed significant changes in lipid and lipid-like metabolites, including ceramide, sphingosine, and sphingosine-1-phosphate (S1P), compared to untreated samples.
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Sphingosine kinase-1 (SPK1), a key enzyme in S1P synthesis, has been implicated in imatinib resistance in GIST cells according to KEGG analysis.
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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DMS (SPK1 inhibitor) improved the efficacy of imatinib in GIST T1 cells .
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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In imatinib-resistant GIST 48R cells with secondary mutations in KIT (V560D + D820A), overexpression of fatty acid synthase (FASN) plays a critical role in promoting growth and migration, as well as sustaining resistance to imatinib.
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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C75 (FASN inhibitor) led to changes in proliferation and apoptosis, but this inhibition also resulted in ERK hyperactivation .
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Glutathione peroxidase 4 (GPX4) is an enzyme that converts lipid hydroperoxides into non-toxic lipids and alcohols.
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Higher levels of GPX4 and GSH were observed in imatinib-resistant GIST T1R cells (exon 11 deletion + D820Y) compared with imatinib-sensitive controls.
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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The high level of GPX4 could contribute to the resistance of GIST T1R to RSL3 (GPX4 inhibitor) .
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Transferrin receptor (TFRC) is a cell surface receptor essential for cellular iron uptake.
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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KEGG analysis indicates that TFRC-related genes were closely associated with metabolic pathways such as pyrimidine metabolism, purine metabolism, OXPHOS, and glycolysis/gluconeogenesis.
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Data mining from the Gene Expression Omnibus (GEO) database revealed that TFRC expression was upregulated in high-risk GIST patients and was indicative of a poor prognosis for recurrence .
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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TFRC may be considered as a potential therapeutic target for GIST.
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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In this category, with drug concentrations around the IC50 for GIST cells, hyperactivated KIT-mediated signaling pathways are only partially inhibited.
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Consequently, cell proliferation, metabolic pathways and disease progression are less affected due to insufficient drug concentrations.
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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For instance, the blood concentration of imatinib is typically 1–2 µM , while the IC50 of imatinib for KIT mutants (double mutations in exon 11 and 17) was 1.2 µM .
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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As a result, 400 mg/day of imatinib has shown no effect on disease control for GIST patients with secondary mutations in clinical trials .
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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An untargeted metabolomic analysis of GIST xenograft samples treated with imatinib revealed that imatinib-resistant samples (KIT) exhibited the fewest number of statistically significant metabolites compared to imatinib-sensitive GIST samples (KIT and KIT) , confirming that imatinib has a reduced effect on imatinib-resistant cells.
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Comparison of imatinib-resistant xenograft GIST samples (KIT) in the presence or absence of imatinib treatment showed that the most downregulated metabolite-related pathways were purine and pyrimidine metabolism and unsaturated fatty acid biosynthesis .
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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The glutamate metabolism pathway was also affected by imatinib treatment .
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Glutaminase in the glutamate metabolism pathway converts glutamine to glutamate, and CB-839 (glutaminase inhibitor) had been tested on solid tumors, including GIST (NCT02071862).
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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In imatinib-resistant GIST T1R (IC50: 5 µM) and 882R (IC50: 5 µM) cells, no increase of OXPHOS proteins was observed following imatinib treatment (1 µM for 48 h) .
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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In imatinib-resistant (IC50: 127 nM) GIST T1R cells (with secondary mutation in PDGFRA, c.1701A > G), GLUT1 in the glycolysis pathway was upregulated under imatinib (13 nM).
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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WZB117 (GLUT1 inhibitor) inhibited the imatinib-resistant phenotype of GIST cells in combination with imatinib (Fig. 4B).
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Under these conditions, co-targeting the metabolism pathway along with imatinib may have limited effectiveness.
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Therefore, a rational increase in drug dosage or switching to other approved TKIs could be beneficial.
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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When KIT/PDGFRA is completely inhibited at drug concentrations significantly above the IC50, most GIST cells undergo apoptosis.
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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However, a small portion of GIST cells enter a cell-cycle-arrested state, exhibiting quiescent-like, senescence-like, and stem-cell-like characteristics that make them resistant to cell death, and capable of repopulation .
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Targeting critical metabolism pathways in these surviving cells could provide a synergistic effect with TKI treatment and improve clinical outcomes.
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Imatinib treatment can decrease glucose uptake by reducing membrane GLUT4 .
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Glucose consumption and lactate production in imatinib-sensitive GIST T1 and 882 cells decreased under imatinib treatment (20 nM, 12 h), indicating a reduction in glycolysis activity .
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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In another study, imatinib (13 nM, 72 h) reduced the expression levels of glycolysis pathway-related molecules, such as GLUT1, HK2, PKM2, and LDH, in GIST T1 (imatinib IC50: 6.5 nM) cells .
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Glycolysis, pentose phosphate pathway, and glutathione metabolism were also reported to be downregulated in imatinib-treated GIST T1 cells.
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Additionally, imatinib combined with RSL3 exhibited promising efficacy in imatinib-sensitive mutants .
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Of note, imatinib (1 µM for 48 h) increased the expression levels of OXPHOS proteins (CII-SDHB, CIII-UQCRC2, CV-ATP5A) in imatinib-sensitive GIST T1 and 882 cells (Fig. 4C).
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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VLX600 (OXPHOS inhibitor) significantly enhanced the efficacy of imatinib in eliminating GIST cells .
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Therefore, OXPHOS could be a promising therapeutic target for imatinib-sensitive GIST patients in combination with adjuvant therapy.
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Developing novel TKIs capable of addressing steric hindrance and the catalytic velocity of oncoproteins offers one solution to overcome drug resistance, such as THE-630 drug .
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Since GIST cells rely heavily on ATP by mutated kinase, strategies that reduce ATP concentrations could enhance TKI efficacy.
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Notably, diabetes has been identified as a poor prognostic factor in GIST patients, likely due to the elevated blood glucose levels that fuel cancer cells [112, 113].
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
|
Targeting glucose metabolism pathways has shown potential to deprive cancer cells of the energy necessary for proliferation.
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Early in vitro studies have demonstrated the promise of this approach, and dietary interventions to restrict blood glucose concentration may further reduce ATP levels, increasing sensitivity to TKIs .
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Tumor heterogeneity presents another hurdle for TKI therapy.
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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After molecular genetic testing on tumor biopsy, careful selection and combination of approved TKIs with appropriate dosing schemes could help effectively target multiple secondary mutations in KIT/PDGFRA .
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Furthermore, combination of adjuvant therapy with TKIs that target downstream signaling pathways, such as PI3K/AKT, MAPK/ERK, or cell cycle regulators, may enhance the therapeutic effect and offer a more comprehensive blockade of hyperactivated pathways.
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Although the potential toxicity of combination therapies is a concern, lower concentration of drugs in combination could provide better inhibition and lower toxicity than a single drug.
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Additionally, the reversibility of binding exhibited by most currently approved TKIs contributes to the persistence of GIST cells.
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PMC11541409
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Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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The reversible nature of currently approved TKIs allows for the leaky activation of oncoproteins, contributing to GIST cell survival and resistance.
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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The development of the type II covalent TKIs, which form irreversible bonds with their targets, could greatly enhance the inhibition efficacy and reduce drug resistance.
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
|
Another innovative strategy involves antibody–drug conjugates (ADCs), which could be a promising method for targeting both wild-type and mutated KIT/PDGFRA, as mutations in these proteins rarely occur in the ligand-binding sites.
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
|
However, clinical trials need to conduct to find which subtype(s) of GIST patients may benefit most from ADC therapy.
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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CAR T-cell therapy also demonstrated potential in the treatment of GIST, although the tumor microenvironment, particularly immunosuppressive ligands or inhibitory factors expressed by the tumor, remains a challenge.
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Addressing these factors is crucial to introducing CAR T therapy in GIST.
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
|
For wild-type GISTs, ADC (DS-6157a) and kinase inhibitor (Olverembatinib) provide potential to treat these TKI-resistant GISTs.
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
|
Targeting metabolic pathways has shown effects in vitro but has had little impact in mouse models, likely due to insufficient inhibition of the oncoproteins.
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
|
Metabolic inhibition should be combined with TKIs to enhance therapy for GIST.
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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By decreasing energy production, reducing carbon intermediates necessary for biosynthesis, and lowering ATP levels, metabolic inhibition may sensitize GIST cells to TKIs, particularly in patients with TKI-sensitive mutations.
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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As the landscape of GIST treatment continues to evolve, an integrated, multifaceted approach involving novel TKIs, combination therapy and metabolic inhibition, may overcome drug resistance, yield significant therapeutic outcomes for patients with GIST.
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Huang, W., et al., A novel fusion between CDC42BPB and ALK in a patient with quadruple wild-type gastrointestinal stromal tumor.
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Mol Genet Genomic Med, 2022.
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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10(5): p. e1881.This reference is of importance because clearly demonstrates that ALK mutation is one of the oncogenes that contribute to the drug resistance of wild-type GIST in the clinical setting.
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Clearly demonstrates that the non-KIT/PDGFRA mutants are one of the drug resistance mechenisms.
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Chan, A., et al., Final Efficacy Results of Neratinib in HER2-positive Hormone Receptor-positive Early-stage Breast Cancer From the Phase III ExteNET Trial.
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