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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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Approved TKIs for GIST treatment are categorized into two groups: type I and type II kinase inhibitors.
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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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Type I TKIs occupy the conserved ATP-binding site and extend into different proximal regions.
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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, they usually have low selectivity due to the conserved nature of ATP-binding site among different types of kinases [32, 33].
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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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Sunitinib and avapritinib fall into this category.
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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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Type II TKIs occupy both the ATP-binding site and an allosteric site, which increases their selectivity.
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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, regorafenib, and ripretinib are type II 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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Currently, all TKIs bind to KIT/PDGFRA mutants in a noncovalent manner, which allows cytosolic ATP (5–10 mM) to enter the ATP-binding site and be utilized by the catalytic center to phosphorylate itself and downstream substrates (Fig. 2C).
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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 "leaky" activation contributes to the survival, if not the proliferation, of GIST cells under TKI 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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Covalent-binding TKIs could potentially address the limitations associated with non-covalent TKIs by forming an irreversible chemical bond with the catalytic center through their electrophilic groups and nucleophilic amino acids (such as cysteine, serine, and threonine) surrounding the catalytic center .
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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, this strategy has not been investigated for GIST, unlike in the cases of BTK, EGFR and HER2 where covalent TKIs are approved for therapy [35–37].
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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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Covalent-binding TKIs generally have higher potency than reversible inhibitors, as they provide prolonged inhibition of signaling 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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Their potential to form a covalent bond with the non-target wild-type kinase may result in increased toxic effects compared to reversible 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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However, this potential toxicity can be mitigated through chemical group modification on the TKIs [39, 40].
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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 settings, multiple KIT/PDGFRA mutants with varying sensitivity to individual TKI (tumor heterogeneity) after imatinib treatment exist in the tumor tissue and thus contribute to resistance of 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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Other drug resistance mechanisms for KIT/PDGFRA-mutant GISTs have also been identified.
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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 FGF/FGFR axis has been shown to reactivate the MAPK/ERK pathway which is previously inhibited by imatinib, and supports the survival 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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Upregulated expression of MET receptor is observed in imatinib-resistant GIST H209 cells (exon 11 + 17 mutations) and contributes 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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The underlying resistance mechanism is that growth factor-activated RTKs (FGFR, MET) share the MAPK/ERK pathway with KIT/PDGFRA, and activation of these RTKs by ligands supports survival and proliferation of GIST cells in the context of TKI 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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Another resistance mechanism involves cellular quiescence.
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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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Quiescent cells evade drug-induced cytotoxicity by arresting cell cycle at the G0 phase, rendering them less susceptible to 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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The DREAM complex has been implicated in maintaining quiescence in residual GIST T1 cells under imatinib treatment, contributing to drug resistance .
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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 non-KIT/PDGFRA-mutant GISTs, these cancer cells are naturally resistant to adjuvant therapy, because oncogenic pathways in these subtypes of GISTs are not the targets of approved TKI drugs.
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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 findings underscore the multifaceted nature of drug resistance in GISTs, involving both genetic mutations and adaptive cellular 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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Understanding these drug-resistance mechanisms is crucial for developing more effective treatment methods.
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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, a drug specifically designed to target the BCR-ABL oncoprotein in chronic myeloid leukemia, has also proven effective for primary GISTs (Fig. 3A).
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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 exon 11 KIT mutations in GIST, found in about 65% of cases, are highly 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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In analysis of prospectively collected data of patients with advanced GIST with known mutational status (KIT/PDGFRA) and treated with imatinib (344 patients), median follow-up was 5.2 years, median progression-free survival (mPFS) was 40.6 months (95% CI: 32.8–48.5), median overall survival (mOS) was 82.4 months (95% CI: 67.7–97.1) .
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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 gastric GIST, female gender (HR 0.60; 95% CI 0.37–0.97) and KIT exon 11 point mutations (HR 0.22; 0.70–0.73) correlated with longer PFS, female gender and no PDGFRA exon 18 D842V (HR 0.32; 0.14–0.71) were factors associated with OS; for non-gastric GIST, KIT exon 11 mutation (557–558 deletions, point mutations, other KIT exon 11 alternations) (HR 0.40; 0.23–0.70) and no PDGFRA exon 18 D842V mutation (HR 0.11; 0.04–0.34) correlated with longer PFS, KIT exon 11 other deletions/indels/duplications (HR 0.57; 0.36–0.88) were factors associated with OS .
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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 parallel, a clinical trial in South Korea identified several prognostic factors for poor PFS, including male gender (HR = 3.4, p = 0.01), the presence of extra-hepatic metastasis (HR = 4.3, p < 0.01), and a primary genotype other than the KIT exon 11 mutation (HR = 7.3, p < 0.01) .
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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 phase III clinical trial on patients with KIT-positive GIST removed at surgery, recurrence-free survival (RFS) was longer in the 36-month imatinib group compared with the 12-month imatinib group (5-year RFS, 65.6% vs 47.9%) .
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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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Another clinical trial evaluated 6 years vs. 3 years of adjuvant imatinib in patients with localized GIST at high risk of relapse (136 enrolled, NCT02260505).
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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 results demonstrated that extending adjuvant imatinib treatment from the recommended 3 years duration to 6 years significantly reduced risk of recurrence, providing further evidence for the benefit of extended therapy duration .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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3Targeted therapy 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. Current approved adjuvant therapies 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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B. Emerging TKIs targeting MAPK/ERK, PI3K/AKT, mTORC1, and the cell cycle.
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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. Therapeutic antibodies 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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D. Antibody–drug conjugates for GIST 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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Targeted therapy in 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. Current approved adjuvant therapies 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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B. Emerging TKIs targeting MAPK/ERK, PI3K/AKT, mTORC1, and the cell cycle.
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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. Therapeutic antibodies 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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D. Antibody–drug conjugates for GIST 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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Sunitinib is used as a second-line therapy when imatinib is ineffective.
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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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It is particularly useful for mutations involving the cytosolic JM domain (exon 11) and/or the ATP-binding site (exon 13/14) [8, 50].
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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 phase III clinical trial evaluating safety and efficacy of sunitinib (50 mg/day, 4 weeks on and 2 weeks off) on patients with histologically proven GIST after imatinib treatment failure due to resistance or intolerance, median follow-up was 41.7 months (95% CI: 40.3–43.8), final mOS analysis for sunitinib (n = 243) versus placebo (n = 118) (without cross-over of placebo-treated patients to open-label sunitinib) was 72.7 weeks (95% CI, 61.3–83.0) versus 39.0 weeks (95% CI, 28.0–54.1).
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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 median time to progression (mTTP) was 26.6 weeks in the sunitinib group (95% CI, 16.0–32.1) versus 6.4 weeks in the placebo group (95% CI: 4.4–10.0) .
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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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Regorafenib, considered a third-line therapy, has not shown superior efficacy compared to sunitinib for mutations involving JM domain (exon 11) and/or ATP-binding site (exon 13/14) but demonstrates potency against mutations involving extracellular domain (exon 9) and/or activation loop (exon 17) [8, 50].
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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 phase III clinical trial (NCT01271712, 199 patients analyzed) evaluating efficacy and safety of regorafenib for patients with metastatic or unresectable GIST and failure of at least previous imatinib and sunitinib, mPFS was 4.8 months for regorafenib (n = 133) and 0.9 months for placebo (n = 66), providing evidence that this highly refractory GIST population can benefit from regorafenib 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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Another clinical trial analyzing the efficacy of regorafenib on different genotypes in patients with advanced GIST refractory to imatinib and/or sunitinib (62 patients enrolled) found that, in the subpopulation with secondary mutations, exon 17/18 mutations exhibited longer mPFS (7.3 vs. 1.9 months, p = 0.001) and longer mOS (20.3 vs. 7.7 months, p = 0.059) than non-activation loop 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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Ripretinib, a fourth-line therapy, has shown broad efficacy against most mutant types of KIT/PDGFRA, with moderate inhibition of JM domain and ATP-binding site 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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In a phase III trial (NCT03353753) on 129 patients with advanced GIST who received prior treatment with at least imatinib, sunitinib, and regorafenib, ripretinib as a fourth-line therapy was generally well tolerated and improved mPFS over placebo (6.3 vs. 1 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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However, in a phase III clinical trial (NCT03673501), ripretinib demonstrated a mPFS of 8.0 months, which was comparable but not superior to sunitinib (8.3 months) as a second-line treatment for advanced 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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Final overall survival (OS) analysis from the same trial (NCT03673501) showed that similar efficacy of mOS existed in the ripretinib group (35.5 months) and the sunitinib groups (31.5 months) for all patients.
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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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Importantly, ripretinib demonstrated a better safety profile compared to sunitinib, making it a promising alternative as a second-line therapy drug for long-term management of advanced 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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Avapritinib is specifically used for patients with PDGFRA exon 18 D842V mutation .
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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 (NCT02508532), among patients with advanced GIST who had unresectable PDGFRA D842V or other mutant GIST who progressed on imatinib and ≥ 1 other TKI, for 4L + population (primarily KIT, median 4 prior TKI) patients (n = 111), avapritinib achieved an objective response rate (ORR) of 22%, with 52 patients achieving stable disease (SD) and a median duration of response (mDOR) of 10.2 months (95% CI: 7.2-∞); for patients with PDGFRA exon 18 mutation who had undergone one prior TKI treatment (n = 43), avapritinib showed an impressive ORR of 86%, with mDOR not yet reached (95% CI: 11.3-∞) .
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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 clinical trial evaluated the long-term efficacy, tolerability and overall survival in patients with unresectable or metastatic PDGFRA D842V-mutant GIST treated with avapritinib (38 patients enrolled), results demonstrated that 300–400 mg/day achieved an ORR of 95%, with a complete response (CR) of 13% (5/38 patients) and partial response (PR) of 82% (31/38 patients), confirming the efficacy of avapritinib in targeting PDGFRA D842V-mutant GIST (regardless of prior 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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Despite these approved TKIs to address the insensitivity of KIT/PDGFRA mutants, tumor heterogeneity with multiple mutants in patient samples presents as an additional challenge .
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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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Combination of TKIs could be a possible strategy to tackle this problem.
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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 phase IB clinical trial (NCT02164240) (n = 13) was conducted to evaluate the safety and effectiveness of rapid alternation of sunitinib and regorafenib on metastatic and/or unresectable GIST with prior failure to at least imatinib, sunitinib, and regorafenib (fourth-line and beyond), SD was observed in 4 patients, mPFS was 1.9 months (95% CI, 1.4–3.6 months), mOS was 10.8 months (95% CI, 5.9-∞).
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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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The study also found early decrease and prolonged suppression of circulating tumor DNA (ctDNA) (KIT primary and/or secondary mutations) until clone reemergence at disease 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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At the molecular level, inhibition of relevant membrane receptor tyrosine kinases (RTKs) such as VEGFR, KIT, PDGFR, FGFR, MET, FLT3, and AXL offers the potential to reverse the resistance phenotype in advanced GIST by inhibiting activation and re-activation of MAPK/ERK and PI3K/AKT 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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Several multi-targeted TKIs are undergoing 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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Anlotinib (an inhibitor of KIT, VEGFR, PDGFR, and FGFR) showed intermediate inhibitory efficacy against GIST cells with KIT mutation in vitro (IC50 > 500 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 a phase II clinical trial (64 patients enrolled) (NCT04106024) evaluating the activity of anlotinib (12 mg/kg/day) on GIST patients who failed the first-line imatinib treatment, 7/64 patients (10.9%) had partial response, 39/64 patients (60.9%) patients had stable disease, mPFS was 8.0 months (95% CI, 4.7–11.3 months) and mOS was not reached.
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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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They reported no statistical significance compared with the PFS of sunitinib at the same period for patients after imatinib failure .
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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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Nilotinib inhibits the activation of ABL1/BCR-ABL1, KIT, PDGFRs, and the discoidin domain receptor.
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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 phase III clinical trial on patients with confirmed unresectable or metastatic GIST and had not received previous systemic therapy for GIST or had a recurrence of GIST 6 months or more after stopping imatinib treatment (647 patients enrolled), 2-year PFS of nilotinib group (324 patients, 400 mg/day) (51.6%) showed no superior efficacy than imatinib group (320 patients, 400 mg/day) (59.2%) as first-line therapy for 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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THE-630, a promising pan-mutant KIT inhibitor designated as an orphan drug for GISTs, showed potent activity against all classes of KIT mutations (exon 11 deletion, exon 9 insertion, exon13/14 mutation, exon18 mutation, secondary mutations including exon 9 + 13 and exon 9 + 18) in vitro (IC50 < 50 nM) and inhibitory efficacy in mouse 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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In a phase I/II clinical trial (NCT05160168) on advanced GIST (unresectable or metastatic) previously treated with imatinib and ≥ 1 additional TKI, THE-630 achieved stable disease at doses of 9 mg/day (3/3 patients) and 12 mg/day (3/3 patients) with reduced KIT-mutant allele fractions in ctDNA .
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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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NB003 targets KIT/PDGFRA with primary and secondary 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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In a phase I clinical trial (NCT04936178) in patients with advanced GIST who progressed on or intolerant to imatinib and other standard of care, NB003 showed a manageable safety profile, the ORR was 26.2% (11/42 patients) and KIT-mutant allele fractions in ctDNA (10/11 patients) were reduced .
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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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Olverembatinib is a multitargeted TKI with promising preclinical activity against 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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In a phase I study (NCT03594422) on patients with TKI-resistant, metastatic, SDH-deficient GISTs, 5/20 patients experienced PR and clinical benefit rate (CR + PR + SD > 4 cycles) was 93.8% for patients receiving > 4 cycles of olverembatinib, implying antitumor activity of olverembatinib in patients with TKI-resistant SDH deficient 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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Approved TKIs for GISTs inhibit the “initiator” of oncogenic signaling cascades.
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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, from a practical viewpoint, inhibiting the initiator alone is often inadequate for the long-term suppression of GIST cells both in vitro and in vivo.
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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The leaky activation of signaling pathways due to non-covalent binding of TKIs or re-activation of other RTKs is sufficient for the survival of cancer cells (Fig. 2C).
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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TKIs targeting the PI3K/AKT pathway, MAPK/ERK pathway, mTORC1 pathway, and cell cycle pathway have been reported in GISTs [68–72] (Fig. 3B).
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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These inhibitors have demonstrated efficacy in preclinical experiments, either alone or in combination with 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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In a phase II clinical trial evaluating safety and efficacy of everolimus (a PI3K/mTOR inhibitor) in combination with imatinib on advanced GIST patients, for patients with imatinib failure alone (stratum1, 23 patients for analysis), 4/23 (17%) were progression free at 4 months; for patients with failure of imatinib and other TKI or cyclin-dependent kinase inhibitors (stratum2, 35 patients for analysis), 13/35 (37%) were progression free at 4 months.
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Both stratums met the predefined criteria for PFS .
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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In a phase IB trial (60 patients enrolled, NCT01468688) on patients who failed prior therapy with imatinib and sunitinib, no PR or CR was observed in the combination group (imatinib and buparlisib (PI3K inhibitor)), SD was observed in 19 patients (54.3%) .
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Combining these inhibitors with approved TKIs provide a possible strategy to overcome the drug-resistance phenotype, as they further block the leaked and reactivated pro-survival signals from oncoproteins or RTKs under non-covalent TKI adjuvant therapy.
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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When selecting targets, upstream kinases or components in the oncogenic signaling cascade should be prioritized.
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Downstream signaling pathways are intertwined and complex, and inhibition of downstream kinases can lead to the reactivation of upstream kinases.
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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For example, ERK inhibition can result in feedback reactivation of the MAPK pathway via RAS/CRAF [75, 76].
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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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Pimitespib inhibits HSP90 by competitively blocking HSP90 enzymatic activity and disrupts the formation of the correct conformation of nascent KIT protein.
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Pimitespib shows efficacy against imatinib-sensitive and -insensitive GIST cells with KIT mutations, both in vitro and in vivo .
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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In a phase III trial (CHAPTER-GIST-301) involving patients with progressive disease (PD) or intolerance after treatment with imatinib, sunitinib, and regorafenib, patients treated with pimitespib (160 mg/day) had a mPFS of 2.8 months (95% CI: 1.6–2.9) (n = 46) versus 1.4 months (95% CI: 0.9–1.8 months) in placebo group (n = 27) , showing efficacy in patients refractory to multiple TKIs.
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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A phase I clinical study (NCT05245968) is underway to evaluate the safety and preliminary efficacy of different treatment regimens in patients with imatinib-refractory GIST in the second-line setting: PIMI (pimitespib 120 mg on 5 days on/2 days off) with imatinib (400 mg/day), PIMI monotherapy and standard therapy sunitinib (50 mg, 4 weeks on/2 weeks off) .
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PMC11541409
|
Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.
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Selinexor inhibits exportin1-mediated nuclear export of RNA, and demonstrates efficacy on imatinib-sensitive and -insensitive GIST cells both in vitro and in vivo .
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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 phase IB/II study (NCT04138381) involving imatinib-resistant GIST patients, the toxicity of selinexor was manageable, clinical benefit rate (CR + PR + SD) ≥ 16 weeks was 42% (95% CI: 0.181–0.685) in cohort A (n = 12, imatinib 400 mg/day, weekly selinexor) and 28% (95% CI: 0.213–0.354) in cohort B (n = 18, selinexor 60 mg twice weekly) .
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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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Guadecitabine (DNA methyltransferase inhibitor) has been tested in clinical trial for SDH-deficient GIST patients to decrease hypermethylation, but it did not achieve the target response rate of 30% of patients .
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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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Further research is needed to verify this therapeutic strategy.
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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, the majority of cases contain wild-type or mutated KIT/PDGFRA, which serves as an ideal target for antibody-based drugs.
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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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Therapeutic antibodies block the binding of ligands to their cognate receptors and induce antibody/complement-dependent cell cytotoxicity (ADCC/CDC) (Fig. 3C).
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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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Blocking the complex formation of SCF/KIT and PDGF/PDGFRA has limited efficacy, as approximately 85% of GIST patients have KIT or PDGFRA mutants, which is independent of ligands.
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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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Regarding ADCC/CDC, these cytotoxicity mechanisms rely on the function of leukocytes (NK cells, macrophages, and γδ T cells) and the complement system [83, 84].
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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, tumor microenvironment in GIST also contains immunosuppressive cytokines/factors, and GIST cells express immunosuppressive ligands on their membranes, both of which inhibit the cytotoxic function of immune cells [85, 86].
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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 humanized anti-KIT antibody, CK6, demonstrated little inhibitory effect in GIST mouse models .
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