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 Emmett, Alan G. Marshall & 2 others Hui Min Zhang, George D. Demetri

Research output: Contribution to journalArticle

237 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Gastrointestinal Stromal Tumors
Drug Resistance
Phosphotransferases
Receptor Protein-Tyrosine Kinases
Mutant Proteins
Mutation
sunitinib
Imatinib Mesylate
Proteins

Keywords

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

ASJC Scopus subject areas

  • General

Cite this

KIT kinase mutants show unique mechanisms of drug resistance to imatinib and sunitinib in gastrointestinal stromal tumor patients. / Gajiwaia, Ketan S.; Wu, Joe C.; Christensen, James; Deshmukh, Gayatri D.; Diehl, Wade; Dinitto, Jonathan P.; English, Jessie M.; Greig, Michael J.; He, You Ai; Jacques, Suzanne L.; Lunney, Elizabeth A.; McTigue, Michele; Molina, David; Quenzer, Terri; Wells, Peter A.; Yu, Xiu; Zhang, Yan; Zou, Aihua; Emmett, Mark; Marshall, Alan G.; Zhang, Hui Min; Demetri, George D.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 5, 03.02.2009, p. 1542-1547.

Research output: Contribution to journalArticle

Gajiwaia, KS, Wu, JC, Christensen, J, Deshmukh, GD, Diehl, W, Dinitto, JP, English, JM, Greig, MJ, He, YA, Jacques, SL, Lunney, EA, McTigue, M, Molina, D, Quenzer, T, Wells, PA, Yu, X, Zhang, Y, Zou, A, Emmett, M, Marshall, AG, Zhang, HM & Demetri, GD 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, vol. 106, no. 5, pp. 1542-1547. https://doi.org/10.1073/pnas.0812413106
Gajiwaia, Ketan S. ; Wu, Joe C. ; Christensen, James ; Deshmukh, Gayatri D. ; Diehl, Wade ; Dinitto, Jonathan P. ; English, Jessie M. ; Greig, Michael J. ; He, You Ai ; Jacques, Suzanne L. ; Lunney, Elizabeth A. ; McTigue, Michele ; Molina, David ; Quenzer, Terri ; Wells, Peter A. ; Yu, Xiu ; Zhang, Yan ; Zou, Aihua ; Emmett, Mark ; Marshall, Alan G. ; Zhang, Hui Min ; Demetri, George D. / KIT kinase mutants show unique mechanisms of drug resistance to imatinib and sunitinib in gastrointestinal stromal tumor patients. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 5. pp. 1542-1547.
@article{ec746fdf78e54867aa18c79a99194889,
title = "KIT kinase mutants show unique mechanisms of drug resistance to imatinib and sunitinib in gastrointestinal stromal tumor patients",
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.",
keywords = "Cancer, Kinase inhibitor, Signal transduction, Targeted therapy resistance mechanism",
author = "Gajiwaia, {Ketan S.} and Wu, {Joe C.} and James Christensen and Deshmukh, {Gayatri D.} and Wade Diehl and Dinitto, {Jonathan P.} and English, {Jessie M.} and Greig, {Michael J.} and He, {You Ai} and Jacques, {Suzanne L.} and Lunney, {Elizabeth A.} and Michele McTigue and David Molina and Terri Quenzer and Wells, {Peter A.} and Xiu Yu and Yan Zhang and Aihua Zou and Mark Emmett and Marshall, {Alan G.} and Zhang, {Hui Min} and Demetri, {George D.}",
year = "2009",
month = "2",
day = "3",
doi = "10.1073/pnas.0812413106",
language = "English (US)",
volume = "106",
pages = "1542--1547",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "5",

}

TY - JOUR

T1 - KIT kinase mutants show unique mechanisms of drug resistance to imatinib and sunitinib in gastrointestinal stromal tumor patients

AU - Gajiwaia, Ketan S.

AU - Wu, Joe C.

AU - Christensen, James

AU - Deshmukh, Gayatri D.

AU - Diehl, Wade

AU - Dinitto, Jonathan P.

AU - English, Jessie M.

AU - Greig, Michael J.

AU - He, You Ai

AU - Jacques, Suzanne L.

AU - Lunney, Elizabeth A.

AU - McTigue, Michele

AU - Molina, David

AU - Quenzer, Terri

AU - Wells, Peter A.

AU - Yu, Xiu

AU - Zhang, Yan

AU - Zou, Aihua

AU - Emmett, Mark

AU - Marshall, Alan G.

AU - Zhang, Hui Min

AU - Demetri, George D.

PY - 2009/2/3

Y1 - 2009/2/3

N2 - 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.

AB - 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.

KW - Cancer

KW - Kinase inhibitor

KW - Signal transduction

KW - Targeted therapy resistance mechanism

UR - http://www.scopus.com/inward/record.url?scp=60849113175&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=60849113175&partnerID=8YFLogxK

U2 - 10.1073/pnas.0812413106

DO - 10.1073/pnas.0812413106

M3 - Article

VL - 106

SP - 1542

EP - 1547

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 5

ER -