The DOI matches its Crossref record; 22 of the 22 references it cites were found in a registry or an index.
KIT kinase mutants show unique mechanisms of drug resistance to imatinib and sunitinib in gastrointestinal stromal tumor patients
Open accessAbstract
Most gastrointestinal stromal tumors (GISTs) exhibit aberrant activation of the receptor tyrosine kinase (RTK) KIT. The efficacy of the inhibitors imatinib mesylate and sunitinib malate in GIST patients has been linked to their inhibition of these mutant KIT proteins. However, patients on imatinib can acquire secondary KIT mutations that render the protein insensitive to the inhibitor. Sunitinib has shown efficacy against certain imatinib-resistant mutants, although a subset that resides in the activation loop, including D816H/V, remains resistant. Biochemical and structural studies were undertaken to determine the molecular basis of sunitinib resistance. Our results show that sunitinib targets the autoinhibited conformation of WT KIT and that the D816H mutant undergoes a shift in conformational equilibrium toward the active state. These findings provide a structural and enzymologic explanation for the resistance profile observed with the KIT inhibitors. Prospectively, they have implications for understanding oncogenic kinase mutants and for circumventing drug resistance.
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Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors
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Self-citationClinical Resistance to STI-571 Cancer Therapy Caused by BCR-ABL Gene Mutation or Amplification
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Self-citationThe T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP
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Biology of Gastrointestinal Stromal Tumors
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Cited by
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Self-citationCircumventing cancer drug resistance in the era of personalized medicine
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Dual or multi-targeting inhibitors: The next generation anticancer agents
Raghavendra, N. M., Pingili, D., Kadasi, S., Mettu, A., & Prasad, S. V. U. M. (2018) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2017.10.021 · Cited by 333
Metadata
- Authors
- Gajiwala, K. S., Wu, J. C., Christensen, J., Deshmukh, G. D., Diehl, W., DiNitto, J. P., English, J. M., Greig, M. J., He, Y.-A., Jacques, S. L., Lunney, E. A., McTigue, M., Molina, D., Quenzer, T., Wells, P. A., Yu, X., Zhang, Y., Zou, A., Emmett, M. R., Marshall, A. G., Zhang, H.-M., & Demetri, G. D.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2009-02-03
- Volume
- 106
- Issue
- 5
- Pages
- 1542-1547
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2116978122
- Cited by
- 391
- References
- 22
- FWCI
- 34.26
- Type
- journal article
- Language
- en
- Open access
- green
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- The paper
- Gajiwala, K. S., Wu, J. C., Christensen, J., Deshmukh, G. D., Diehl, W., DiNitto, J. P., English, J. M., Greig, M. J., He, Y.-A., Jacques, S. L., Lunney, E. A., McTigue, M., Molina, D., Quenzer, T., Wells, P. A., Yu, X., Zhang, Y., Zou, A., Emmett, M. R., . . . Demetri, G. D. (2009). KIT kinase mutants show unique mechanisms of drug resistance to imatinib and sunitinib in gastrointestinal stromal tumor patients. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.0812413106
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Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
