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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Corresponding suggestions are proposed to overcome drug-resistance phenotype of 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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This review also summarizes the suitability of currently approved TKIs on different KIT/PDGFRA mutations and updates related 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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Recent potent drugs and emerging strategies against advanced GISTs in clinical trials are presented.
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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, metabolic intervention offers a new avenue for clinical management 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 landscape of metabolism in GIST and metabolic changes under imatinib treatment are summarized based on currently published data.
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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 OXPHOS pathway is a promising therapeutic target in combination with TKI against sensitive KIT/PDGFRA 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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Comprehensive understanding of the above resistance mechanisms, experimental drugs/strategies and metabolic changes is critical to implement the proper therapy strategy and improve the clinical therapy outcomes for GIST.Gastrointestinal stromal tumor (GIST) is a type of sarcoma that originates from precursor cell of the interstitial cells of Cajal (ICC) .
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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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Before the identification of specific oncogenic mutations in GIST, surgical resection was the primary treatment option.
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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 five-year survival rate for localized GIST was approximately 54%, while cases with incomplete resections or unresectable tumors had a median survival of about 22 months .
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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 identification of KIT and PDGFRA mutations defines GISTs as a unique cancer type [3, 4].
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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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Approximately 85% of GIST cases harbor gain-of-function mutations (GOF) in KIT and PDGFRA genes.
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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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These mutations have become critical therapeutic targets, leading to the development of tyrosine kinase inhibitors (TKIs) such as imatinib, sunitinib, regorafenib, ripretinib, and avapritinib.
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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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Combining surgery with TKI therapy has increased the five-year survival rate to 92% for localized GISTs and 50% for metastatic cases .
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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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Despite the success of TKI therapy, challenges such as drug resistance and disease progression remain persistent.
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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 mechanisms of drug resistance are caused by multiple reasons in the context of 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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Based on available data, we discuss the current drug resistance mechanisms and their underlying molecular basis.
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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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Strategies to overcome the above resistance were proposed and discussed.
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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 related to the current approved TKIs and new emerging therapeutic drugs are presented.
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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 are also summarized and analyzed in order to find possible therapeutic targets to benefit the therapy of 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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Through this review, we hope to offer fresh insights that could benefit future therapy strategies, drug development, management of GISTs in clinical, leading to better therapeutic outcomes in patients with 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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GOF mutations in KIT were observed in a major proportion (about 80%) in patients with GIST, and play crucial roles in GIST tumorigenesis and progression .
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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 most common KIT mutations occur in exon 11, affecting the cytosolic juxtamembrane domain (Fig. 1B).
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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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Mutation types include point(s) mutation, insertions and peptide deletions that disrupt the binding of the inhibitory JM to the tyrosine kinase domain (TKD) .
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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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Exon 11 mutations render tumors sensitive 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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GIST cell lines (GIST 430 and GIST T1) are sensitive to imatinib (IC50: 30–60 nM) , as does the mast cell line HMC1.1 (IC50: 10.7 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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Clinically, adjuvant imatinib therapy prolongs the five-year survival of GIST patients harboring exon 11 mutations [10–13].
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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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Exon 9 mutations in the extracellular domain are the second most common KIT mutations.
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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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These alterations mimic the cytosolic conformational rearrangement of wild-type KIT induced by stem cell factor (SCF) (Fig. 1A).
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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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These mutations confer resistance to imatinib, with both in vitro studies and clinical data supporting this observation.
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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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Cell lines transformed by KIT are resistant to imatinib , and patients with these mutations also exhibit resistance to imatinib in clinical setting .
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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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Less common mutations in exon 13/14 (located in TKD N lobe, TKD1) and 17 (located in TKD C lobe, TKD2), enhance ATP binding and/or increase kinase activation velocity, resulting in varying degrees of resistance to imatinib [14, 15].
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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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GIST 882 cells show moderate resistance to imatinib (IC50: 173 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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Other mutations, as in cell lines (P815, Kasumi-1, Ba/F3), show moderate to high resistance to imatinib [8, 9].
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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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These mutations, although rare in primary GIST, often arise as secondary mutations following imatinib treatment, and significantly aggravate the phenomenon of drug resistance (Fig. 1B).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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1Molecular pathology of 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. Schemes of inactivated and activated wild-type oncoprotein (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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B. Mutation pattern of KIT/PDGFRA 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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C. Mutations in wild-type 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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Molecular pathology of GIST.
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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A. Schemes of inactivated and activated wild-type oncoprotein (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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B. Mutation pattern of KIT/PDGFRA 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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C. Mutations in wild-type 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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GOF mutations in PDGFRA, while less frequent (about 5%) than KIT mutations, have a similar mutation pattern like KIT mutants 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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The most common PDGFRA mutations occur in the TKD C lobe (exon 18), resulting in enhanced ATP affinity and/or catalytic velocity (Fig. 1B).
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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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Mutations in exon 18 exhibit various sensitivity 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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Ba/F3 or CHO cells with PDGFRA mutations (D842V, RD841-842KI) are resistant to imatinib, while CHO cells with PDGFRA mutation (D842Y, D846Y, Y849C, Del DIMH842-845, Del DIMH843-846, Del I843 and HDSN845-848P) are sensitive to imatinib (IC50 < 200 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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In clinical trials, patients with PDGFRA are resistant to adjuvant imatinib therapy [9, 17, 18].
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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 second most frequent mutations locate in the cytosolic JM domain (exon 12).
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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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Primary GIST cells with PDGFRA mutations (V561D, SPDHE566-571R and insertion ER561-562) are sensitive to imatinib treatment in vitro (IC50 < 200 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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The third most frequent mutations locate in the TKD N lobe (exon 14).
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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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Cells with PDGFRA mutation are sensitive 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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Mutations in exon 14 often emerge as secondary mutations, which significantly enhance drug resistance in clinical setting .
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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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Approximately 10–15% of GIST cases have no mutations in the KIT/PDGFRA genes and are classified as wild-type (WT) 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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These cases often involve gene alterations in other proteins, such as succinate dehydrogenase (SDH), neurofibromin 1 (NF1), RAS, BRAF, and PIK3CA, all contributing to tumorigenesis [20, 21] (Fig. 1C).
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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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SDH-deficient GISTs, accounting for less than 9% of all cases, represent the third most common GIST subtype [21, 22].
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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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SDH couples the oxidation of succinate to fumarate in the citric acid cycle with the reduction of ubiquinone to ubiquinol in the electron transport chain.
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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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Accumulation of succinate caused by loss-of-function (LOF) SDH mutation inhibits several alpha-ketoglutarate dioxygenases, inducing the pseudohypoxia pathway and causing epigenetic changes that lead to reprogramming of cell metabolism .
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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 GISTs with SDH deficiency, significant hypermethylation has been observed compared to kinase-mutant 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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This hypermethylation pattern is a unifying feature of SDH-deficient GISTs, and methyl-divergence process is not random .
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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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Hypermethylation of two insulators that separate FGFR and KIT from upstream super-enhancers enhances FGFR and KIT expression, which contributes to GIST progression .
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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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Activating mutations in receptor tyrosine kinases (RTKs) and their downstream signaling pathways account for approximately 5% of GIST cases.
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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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FGFR, NTRK, and ALK translocations can act as oncogenic drivers in these subtypes [26, 27].
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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, GOF mutations in BRAF, RAS, or PIK3CA affect key molecules in RTK signaling cascades, contributing to GIST pathogenesis through constant activation of pathways like the MAPK or PI3K 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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Some GIST cases can also result from mutations in the NF1 gene.
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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 NF1 gene encodes neurofibromin 1, which stimulates the GTPase activity of RAS and thus negatively regulates RAS/MAPK signaling pathway.
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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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LOF mutations in NF1 lead to deregulated activation of the RAS/MAPK pathway, contributing to the tumorigenesis of 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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Molecular genetic testing is useful in identifying the underlying genetic mutations in GISTs and assists therapeutic decisions.
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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 information guides prognosis, aids in predicting tumor response to therapy, and understands mechanisms of resistance, allowing for the development of personalized treatment strategies, especially for non-KIT/PDGFRA mutant 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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KIT functions as a receptor for an extracellular ligand (SCF) and as an enzyme (kinase) that catalyzes the transfer of a phosphate group from ATP to tyrosine residues on KIT and downstream proteins.
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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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Mutations in the extracellular and cytosolic JM domains lead to the TKD being in an activation state, thus exempting the KIT mutants from the control of SCF.
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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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Other mutations in TKD enhance its tendency to remain in the activation state and/or increase its catalytic velocity [14, 16, 29, 30].
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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These mutations give KIT different characteristics.
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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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Firstly, the vivid spatial conformation variations in the catalytic center of different KIT mutants create different degrees of steric hindrance, which affects the entry of KIT TKIs [30, 31] (Fig. 2A).
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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, KIT mutants exhibit varying resistance to TKIs inhibition.
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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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Secondly, spatial conformation in the catalytic center of KIT/PDGFRA mutants can lead to increased affinity for ATP (Km[ATP]) and/or enhanced catalytic velocity (Kcat) [14–16] (Fig. 2B).
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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 the enzyme (kinase) activity of KIT/PDGFRA involves transferring phosphate group from ATP to other tyrosine residues, TKIs and ATP compete to occupy the ATP-binding site in the catalytic center (Fig. 2B).
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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 mutants with increased ATP affinity, ATP more readily enters the catalytic center and is utilized by the kinase than TKIs.
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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, higher concentrations of TKIs are needed to achieve the same inhibitory effect toward mutants with increased ATP affinity than toward mutants without increased ATP affinity, thus demonstrating a resistance phenotype.
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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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Fig. 2Drug resistance mechanisms in GIST cells with KIT/PDGFRA mutants, KIT as a model.
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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. Steric hindrance.
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Duplication in exon 9 induces TKD in an activation conformation, which prohibits entry 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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Deletion in exon 11 creates a TKD conformation, which permits imatinib entry.
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Double mutations in exon 11 (deletion) and exon 14 (T670I) create a TKD conformation which prohibit imatinib entry .
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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B. Enhanced affinity for ATP or enhanced catalytic velocity.
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Deletion in exon 11 creates a TKD conformation, which permits imatinib entry.
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Double mutation in exon 11 (deletion) and exon 13/14 (V654A, T670I) create a TKD conformation which could have enhanced affinity for ATP .
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Double mutation in exon 11 (deletion) and exon 17 (activation loop) create a TKD conformation which could have enhanced catalytic velocity and affinity to ATP .
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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C. Leaky activation.
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Reversible binding of imatinib to catalytic center permits leaky entry of ATP and activation of KIT.
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
|
Drug resistance mechanisms in GIST cells with KIT/PDGFRA mutants, KIT as a model.
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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A. Steric hindrance.
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
|
Duplication in exon 9 induces TKD in an activation conformation, which prohibits entry of imatinib .
|
PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
|
Deletion in exon 11 creates a TKD conformation, which permits imatinib entry.
|
PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
|
Double mutations in exon 11 (deletion) and exon 14 (T670I) create a TKD conformation which prohibit imatinib entry .
|
PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
|
B. Enhanced affinity for ATP or enhanced catalytic velocity.
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
|
Deletion in exon 11 creates a TKD conformation, which permits imatinib entry.
|
PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
|
Double mutation in exon 11 (deletion) and exon 13/14 (V654A, T670I) create a TKD conformation which could have enhanced affinity for ATP .
|
PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
|
Double mutation in exon 11 (deletion) and exon 17 (activation loop) create a TKD conformation which could have enhanced catalytic velocity and affinity to ATP .
|
PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
|
C. Leaky activation.
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
|
Reversible binding of imatinib to catalytic center permits leaky entry of ATP and activation of KIT.
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