ArticleCancer research2019
ATP-Competitive Inhibitors Midostaurin and Avapritinib Have Distinct Resistance Profiles in Exon 17-Mutant KIT.
Article in Cancer research, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
20 citing papers in PubMed, 30 citations in OpenAlex.
- [Efficacy and safety analysis of avapritinib in children with RUNX1::RUNX1T1 positive-acute myeloid leukemia with KIT mutations].Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi · 2026Article
- BTK Inhibition in Hematology: From CLL/SLL to Emerging Applications Across B-Cell and Immune Disorders.Biomolecules · 2026Review
- A case report of advanced small intestinal stromal tumor with KIT gene mutation and BRCA2 deletion after multi-line treatments.Frontiers in oncology · 2025Article
- Avapritinib-based SAR studies unveil a binding pocket in KIT and PDGFRA.Nature communications · 2024Article
- The Importance of the Pyrazole Scaffold in the Design of Protein Kinases Inhibitors as Targeted Anticancer Therapies.Molecules (Basel, Switzerland) · 2023Review
- Approved Small-Molecule ATP-Competitive Kinases Drugs Containing Indole/Azaindole/Oxindole Scaffolds: R&D and Binding Patterns Profiling.Molecules (Basel, Switzerland) · 2023Review
- Case Report: Molecular and microenvironment change upon midostaurin treatment in mast cell leukemia at single-cell level.Frontiers in immunology · 2023Article
- Emerging Data on the Safety and Efficacy of Ripretinib for the Treatment of Gastrointestinal Stromal Tumors.Clinical and experimental gastroenterology · 2023Review
- Pyrazole-containing pharmaceuticals: target, pharmacological activity, and their SAR studies.RSC medicinal chemistry · 2022Review
- Assessing the Activation of Tyrosine Kinase KIT through Free Energy Calculations.Journal of chemical theory and computation · 2022Article
- CDK4/CDK6 Inhibitors Synergize with Midostaurin, Avapritinib, and Nintedanib in Inducing Growth Inhibition inCancers · 2022Article
- Review
- Avapritinib for Systemic Mastocytosis.Expert review of hematology · 2021Article
- Gastrointestinal Manifestations in Systemic Mastocytosis: The Need of a Multidisciplinary Approach.Cancers · 2021Review
- Inhibition of KIT Tyrosine Kinase Activity: Two Decades After the First Approval.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2021Article
- A new monoclonal antibody that blocks dimerisation and inhibits c-kit mutation-driven tumour growth.Journal of cancer research and clinical oncology · 2021Article
- Multi-Omics Analysis of the Anti-tumor Synergistic Mechanism and Potential Application of Immune Checkpoint Blockade Combined With Lenvatinib.Frontiers in cell and developmental biology · 2021Article
- Article
- Avapritinib: First Approval.Drugs · 2020Review
- Acute aleukemic mast cell leukemia: Report of a case and review of the literature.Leukemia research reports · 2020Article
Corrections and comments
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Authors and funding
10 authors at 1 institution in 2 countries.
Funding
Abstract
KIT is a type-3 receptor tyrosine kinase that is frequently mutated at exon 11 or 17 in a variety of cancers. First-generation KIT tyrosine kinase inhibitors (TKI) are ineffective against KIT exon 17 mutations, which favor an active conformation that prevents these TKIs from binding. The ATP-competitive inhibitors, midostaurin and avapritinib, which target the active kinase conformation, were developed to inhibit exon 17-mutant KIT. Because secondary kinase domain mutations are a common mechanism of TKI resistance and guide ensuing TKI design, we sought to define problematic KIT kinase domain mutations for these emerging therapeutics. Midostaurin and avapritinib displayed different vulnerabilities to secondary kinase domain substitutions, with the T670I gatekeeper mutation being selectively problematic for avapritinib. Although gatekeeper mutations often directly disrupt inhibitor binding, we provide evidence that T670I confers avapritinib resistance indirectly by inducing distant conformational changes in the phosphate-binding loop. These findings suggest combining midostaurin and avapritinib may forestall acquired resistance mediated by secondary kinase domain mutations. SIGNIFICANCE: This study identifies potential problematic kinase domain mutations for next-generation KIT inhibitors midostaurin and avapritinib.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.