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| Ref Type | Journal Article | ||||||||||||
| PMID | (24205792) | ||||||||||||
| Authors | Zhao J, Quan H, Xu Y, Kong X, Jin L, Lou L | ||||||||||||
| Title | Flumatinib, a selective inhibitor of BCR-ABL/PDGFR/KIT, effectively overcomes drug resistance of certain KIT mutants. | ||||||||||||
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| Abstract Text | Activating mutations in KIT have been associated with gastrointestinal stromal tumors (GISTs). The tyrosine kinase inhibitor imatinib mesylate has revolutionized the treatment of GISTs. Unfortunately, primary or acquired resistance to imatinib does occur in GISTs and forms a major problem. Although sunitinib malate, a multi-kinase inhibitor, has shown effectiveness against imatinib-resistant GISTs, recent studies have indicated that some imatinib-resistant GISTs harboring secondary mutations in the KIT activation loop were also resistant to sunitinib. Therefore, new drugs capable of overcoming the dual drug resistance of GISTs probably have potential clinical utility. In this study, we investigated the efficacy of flumatinib, an inhibitor of BCR-ABL/PDGFR/KIT, against 32D cells transformed by various KIT mutants and evaluated its potency to overcome the drug resistance of certain mutants. Interestingly, our in vitro study revealed that flumatinib effectively overcame the drug resistance of certain KIT mutants with activation loop mutations (i.e., D820G, N822K, Y823D, and A829P). Our in vivo study consistently suggested that flumatinib had superior efficacy compared with imatinib or sunitinib against 32D cells with the secondary mutation Y823D. Molecular modeling of flumatinib docked to the KIT kinase domain suggested a special mechanism underlying the capability of flumatinib to overcome the drug-resistance conferred by activation loop mutations. These findings suggest that flumatinib could be a promising therapeutic agent against GISTs resistant to both imatinib and sunitinib because of secondary mutations in the activation loop. | ||||||||||||
| Molecular Profile | Treatment Approach |
|---|---|
| No data available in table | |
| Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
|---|---|---|---|---|---|
| No data available in table | |||||
| Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
|---|---|---|---|
| Flumatinib | Flumatinib | 15 | 0 |
| Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
|---|---|---|---|---|
| Flumatinib | HH-GV678 | BCR-ABL Inhibitor 32 KIT Inhibitor 57 PDGFR Inhibitor (Pan) 30 | Flumatinib (HH-GV678) inhibits KIT, PDGFR, and BCR-ABL, potentially resulting in decreased tumor cell proliferation (PMID: 24205792, PMID: 31699612). |
| Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
|---|---|---|---|---|---|
| KIT | N822K | missense | gain of function | KIT N822K lies within the activation loop in the protein kinase domain of the Kit protein (PMID: 24205792). N822K results in constitutive activation of Kit, increased Erk1/2 and Stat3 phosphorylation, is transforming in culture (PMID: 24205792, PMID: 31484543), leads to mislocalization of Kit to endolysosomes (PMID: 31484543), and has been identified as a secondary mutation associated with imatinib resistance (PMID: 18488160). | Y |
| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| KIT A502_Y503dup | Advanced Solid Tumor | sensitive | Sunitinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells expressing KIT A502_Y503dup (Y503_F504insAY) were sensitive to Sutent (sunitinib) in culture, demonstrating decreased cell proliferation (PMID: 24205792). | 24205792 |
| KIT A502_Y503dup | Advanced Solid Tumor | sensitive | Flumatinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells expressing KIT A502_Y503dup (Y503_F504insAY) were sensitive to Flumatinib in culture, demonstrating decreased cell proliferation (PMID: 24205792). | 24205792 |
| KIT A502_Y503dup | Advanced Solid Tumor | sensitive | Imatinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells expressing KIT A502_Y503dup (Y503_F504insAY) were sensitive to Gleevec (imatinib) in culture, demonstrating decreased cell proliferation (PMID: 24205792). | 24205792 |
| KIT D816H | Advanced Solid Tumor | predicted - sensitive | Sunitinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells expressing KIT D816H were more sensitive to treatment with Sutent (sunitinib) in culture compared to Gleevec (imatinib) (PMID: 24205792). | 24205792 |
| KIT D816H | Advanced Solid Tumor | predicted - sensitive | Flumatinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells expressing KIT D816H were more sensitive to treatment with Flumatinib in culture compared to Gleevec (imatinib) (PMID: 24205792). | 24205792 |
| KIT D816V | Advanced Solid Tumor | resistant | Sunitinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells expressing KIT D816V were resistant to treatment with Sutent (sunitinib) in culture (PMID: 24205792). | 24205792 |
| KIT D816V | Advanced Solid Tumor | resistant | Flumatinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells expressing KIT D816V were resistant to treatment with Flumatinib in culture (PMID: 24205792). | 24205792 |
| KIT D816Y | Advanced Solid Tumor | resistant | Flumatinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells expressing KIT D816Y were resistant to treatment with Flumatinib in culture (PMID: 24205792). | 24205792 |
| KIT D816Y | Advanced Solid Tumor | resistant | Sunitinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells expressing KIT D816Y were resistant to treatment with Sutent (sunitinib) in culture (PMID: 24205792). | 24205792 |
| KIT D816Y | Advanced Solid Tumor | resistant | Imatinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells expressing KIT D816Y were resistant to treatment with Gleevec (imatinib) in culture (PMID: 24205792). | 24205792 |
| KIT I571_D579dup | Advanced Solid Tumor | predicted - resistant | Flumatinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells expressing KIT I571_D579dup (KIT D579_H580insIDPTQLPYD) were moderately resistant to Flumatinib in culture (PMID: 24205792). | 24205792 |
| KIT I571_D579dup | Advanced Solid Tumor | predicted - resistant | Imatinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells expressing KIT I571_D579dup (KIT D579_H580insIDPTQLPYD) were moderately resistant to Gleevec (imatinib) in culture (PMID: 24205792). | 24205792 |
| KIT I571_D579dup | Advanced Solid Tumor | predicted - resistant | Sunitinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells expressing KIT I571_D579dup (KIT D579_H580insIDPTQLPYD) were moderately resistant to Sutent (sunitinib) in culture (PMID: 24205792). | 24205792 |
| KIT N822K | Advanced Solid Tumor | predicted - sensitive | Flumatinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells expressing KIT N822K were more sensitive to treatment with Flumatinib in culture compared to Gleevec (imatinib), demonstrating decreased cell proliferation (PMID: 24205792). | 24205792 |
| KIT N822K | Advanced Solid Tumor | predicted - sensitive | Sunitinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells expressing KIT N822K were more sensitive to treatment with Sutent (sunitinib) in culture compared to Gleevec (imatinib), demonstrating decreased cell proliferation (PMID: 24205792). | 24205792 |
| KIT N822K | Advanced Solid Tumor | resistant | Imatinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells expressing KIT N822K were resistant to treatment with Gleevec (imatinib) in culture (PMID: 24205792). | 24205792 |
| KIT T417_D419delinsI | Advanced Solid Tumor | conflicting | Imatinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells expressing KIT T417_D419delinsI were resistant to treatment with Gleevec (imatinib) in culture (PMID: 24205792). | 24205792 |
| KIT T417_D419delinsI | Advanced Solid Tumor | sensitive | Sunitinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells expressing KIT T417_D419delinsI were sensitive to treatment with Sutent (sunitinib), demonstrating decreased cell proliferation (PMID: 24205792). | 24205792 |
| KIT T417_D419delinsI | Advanced Solid Tumor | sensitive | Flumatinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells expressing KIT T417_D419delinsI were sensitive to treatment with Flumatinib, demonstrating decreased cell proliferation (PMID: 24205792). | 24205792 |
| KIT V559_V560del | Advanced Solid Tumor | sensitive | Imatinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells expressing KIT V559_V560del were sensitive to Gleevec (imatinib), demonstrating decreased cell proliferation in culture (PMID: 24205792). | 24205792 |
| KIT V559_V560del | Advanced Solid Tumor | sensitive | Flumatinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells expressing KIT V559_V560del were sensitive to Flumatinib, demonstrating decreased cell proliferation in culture (PMID: 24205792). | 24205792 |
| KIT V559_V560del | Advanced Solid Tumor | sensitive | Sunitinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells expressing KIT V559_V560del were sensitive to Sutent (sunitinib), demonstrating decreased cell proliferation in culture (PMID: 24205792). | 24205792 |
| KIT V559D | Advanced Solid Tumor | sensitive | Imatinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells expressing KIT V559D were sensitive to Gleevec (imatinib), demonstrating decreased cell proliferation in culture and inhibition of Kit, Erk1/2, and Stat3 phosphorylation (PMID: 24205792). | 24205792 |
| KIT V559D | Advanced Solid Tumor | sensitive | Sunitinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells expressing KIT V559D were sensitive to Sutent (sunitinib), demonstrating decreased cell proliferation in culture and inhibition of Kit, Erk1/2, and Stat3 phosphorylation (PMID: 24205792). | 24205792 |
| KIT V559D | Advanced Solid Tumor | sensitive | Flumatinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells expressing KIT V559D were sensitive to Flumatinib, demonstrating decreased cell proliferation in culture and inhibition of Kit, Erk1/2, and Stat3 phosphorylation (PMID: 24205792). | 24205792 |
| KIT V559D KIT A829P | Advanced Solid Tumor | sensitive | Flumatinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells co-expressing KIT A829P and KIT V559D were sensitive to Flumatinib in culture, demonstrating decreased cell proliferation and inhibition of Kit, Erk1/2, and Stat3 phosphorylation (PMID: 24205792). | 24205792 |
| KIT V559D KIT A829P | Advanced Solid Tumor | no benefit | Sunitinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells co-expressing KIT A829P and KIT V559D were insensitive to Sutent (sunitinib) in culture (PMID: 24205792). | 24205792 |
| KIT V559D KIT D820G | Advanced Solid Tumor | sensitive | Flumatinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells co-expressing KIT D820G and KIT V559D were sensitive to Flumatinib in culture, demonstrating decreased cell proliferation (PMID: 24205792). | 24205792 |
| KIT V559D KIT N822K | Advanced Solid Tumor | sensitive | Flumatinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells co-expressing KIT N822K and KIT V559D were sensitive to Flumatinib in culture, demonstrating decreased cell proliferation and inhibition of Kit, Erk 1/2, and Stat3 phosphorylation (PMID: 24205792). | 24205792 |
| KIT V559D KIT N822K | Advanced Solid Tumor | no benefit | Sunitinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells co-expressing KIT N822K and KIT V559D were insensitive to Sutent (sunitinib) in culture (PMID: 24205792). | 24205792 |
| KIT V559D KIT T670I | Advanced Solid Tumor | sensitive | Sunitinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells co-expressing KIT V559D and KIT T670I were sensitive to treatment with Sutent (sunitinib) in culture, demonstrating decreased cell proliferation (PMID: 24205792). | 24205792 |
| KIT V559D KIT V654A | Advanced Solid Tumor | sensitive | Sunitinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells co-expressing KIT V559D and KIT V654A were sensitive to treatment with Sutent (sunitinib) in culture, demonstrating decreased cell proliferation (PMID: 24205792). | 24205792 |
| KIT V559D KIT Y823D | Advanced Solid Tumor | no benefit | Sunitinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells co-expressing KIT Y823D and KIT V559D were insensitive to Sutent (sunitinib) in culture and in mouse models (PMID: 24205792). | 24205792 |
| KIT V560D KIT T670I | Advanced Solid Tumor | resistant | Flumatinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells co-expressing KIT V560D and KIT T670I were resistant to Flumatinib in culture (PMID: 24205792). | 24205792 |
| KIT V560D KIT V654A | Advanced Solid Tumor | resistant | Flumatinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells co-expressing KIT V560D and KIT V654A were resistant to Flumatinib in culture (PMID: 24205792). | 24205792 |
| KIT D816V | Advanced Solid Tumor | resistant | Cabozantinib | Preclinical | Actionable | In a preclinical study, transformed cells expressing KIT D816V demonstrated resistance to Cometriq (cabozantinib) in culture (PMID: 24205792). | 24205792 |
| KIT V559D KIT Y823D | Advanced Solid Tumor | no benefit | Imatinib | Preclinical | Actionable | In a preclinical study, Gleevec (imatinib) treatment in a mouse model with cells expressing KIT V559D and KIT Y823D resulted in shortened survival (PMID: 24205792). | 24205792 |
| KIT V559D KIT Y823D | Advanced Solid Tumor | sensitive | Flumatinib | Preclinical | Actionable | In a preclinical study, Flumatinib treatment in transformed cells co-expressing KIT Y823D and KIT V559D resulted in decreased cell proliferation and inhibition of Kit, Erk1/2, and Stat3 phosphorylation in culture, and led to improved survival in mouse models (PMID: 24205792). | 24205792 |
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