KIT kinase mutants show unique mechanisms of drug resistance to imatinib and sunitinib in gastrointestinal stromal tumor patients

Ketan S. Gajiwaia, Joe C. Wu, James Christensen, Gayatri D. Deshmukh, Wade Diehl, Jonathan P. Dinitto, Jessie M. English, Michael J. Greig, You Ai He, Suzanne L. Jacques, Elizabeth A. Lunney, Michele McTigue, David Molina, Terri Quenzer, Peter A. Wells, Xiu Yu, Yan Zhang, Aihua Zou, Mark R. Emmett, Alan G. MarshallHui Min Zhang, George D. Demetri

Research output: Contribution to journalArticle

251 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1542-1547
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number5
DOIs
StatePublished - Feb 3 2009

Keywords

  • Cancer
  • Kinase inhibitor
  • Signal transduction
  • Targeted therapy resistance mechanism

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'KIT kinase mutants show unique mechanisms of drug resistance to imatinib and sunitinib in gastrointestinal stromal tumor patients'. Together they form a unique fingerprint.

  • Cite this

    Gajiwaia, 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 of the United States of America, 106(5), 1542-1547. https://doi.org/10.1073/pnas.0812413106