KIT Kinase Mutants Show Unique Mechanisms of Drug Resistance to Imatinib and Sunitinib in Gastrointestinal Stromal Tumor Patients

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2009 Jan 24

PMID 19164557

Citations 153

Authors

Ketan S Gajiwala

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 Marshall

Hui-Min Zhang

George D Demetri

Affiliations

Soon will be listed here.

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.

Citing Articles

Phase II Study of Sunitinib in Tumors With Mutations: Results From the NCI MATCH ECOG-ACRIN Trial (EAY131) Subprotocol V.

Gien L, Song Z, Poklepovic A, Collisson E, Zwiebel J, Gray R JCO Precis Oncol. 2024; 8:e2400514.

PMID: 39666929 PMC: 11643086. DOI: 10.1200/PO-24-00514.

Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update.

He C, Wang Z, Yu J, Mao S, Xiang X Curr Treat Options Oncol. 2024; 25(11):1390-1405.

PMID: 39441520 PMC: 11541409. DOI: 10.1007/s11864-024-01272-7.

ONCOLINER: A new solution for monitoring, improving, and harmonizing somatic variant calling across genomic oncology centers.

Martin R, Gaitan N, Jarlier F, Feuerbach L, de Soyres H, Arbones M Cell Genom. 2024; 4(9):100639.

PMID: 39216474 PMC: 11480849. DOI: 10.1016/j.xgen.2024.100639.

Efficacy of Trametinib in Neurofibromatosis Type 1-Associated Gastrointestinal Stromal Tumors: A Case Report.

Fukuda M, Mukohara T, Kuwata T, Sunami K, Naito Y JCO Precis Oncol. 2024; 8:e2300649.

PMID: 39116355 PMC: 11371073. DOI: 10.1200/PO.23.00649.

A PDE3A-SLFN12 Molecular Glue Exhibits Significant Antitumor Activity in TKI-Resistant Gastrointestinal Stromal Tumors.

Takaki E, Kiyono K, Obuchi Y, Yamauchi T, Watanabe T, Matsumoto H Clin Cancer Res. 2024; 30(16):3603-3621.

PMID: 38864850 PMC: 11325149. DOI: 10.1158/1078-0432.CCR-24-0096.

References

Gorre M, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao P . Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science. 2001; 293(5531):876-80. DOI: 10.1126/science.1062538. View

Mol C, Dougan D, Schneider T, Skene R, Kraus M, Scheibe D . Structural basis for the autoinhibition and STI-571 inhibition of c-Kit tyrosine kinase. J Biol Chem. 2004; 279(30):31655-63. DOI: 10.1074/jbc.M403319200. View

Heinrich M, Maki R, Corless C, Antonescu C, Harlow A, Griffith D . Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor. J Clin Oncol. 2008; 26(33):5352-9. PMC: 2651076. DOI: 10.1200/JCO.2007.15.7461. View

Zhou T, Parillon L, Li F, Wang Y, Keats J, Lamore S . Crystal structure of the T315I mutant of AbI kinase. Chem Biol Drug Des. 2007; 70(3):171-81. DOI: 10.1111/j.1747-0285.2007.00556.x. View

Heinrich M, Corless C, Blanke C, Demetri G, Joensuu H, Roberts P . Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol. 2006; 24(29):4764-74. DOI: 10.1200/JCO.2006.06.2265. View

Mol C, Lim K, Sridhar V, Zou H, Chien E, Sang B . Structure of a c-kit product complex reveals the basis for kinase transactivation. J Biol Chem. 2003; 278(34):31461-4. DOI: 10.1074/jbc.C300186200. View

Schaub T, Hendrickson C, Horning S, Quinn J, Senko M, Marshall A . High-performance mass spectrometry: Fourier transform ion cyclotron resonance at 14.5 Tesla. Anal Chem. 2008; 80(11):3985-90. DOI: 10.1021/ac800386h. View

Emmett M, Caprioli R . Micro-electrospray mass spectrometry: Ultra-high-sensitivity analysis of peptides and proteins. J Am Soc Mass Spectrom. 2013; 5(7):605-13. DOI: 10.1016/1044-0305(94)85001-1. View

Wu J, Chuan H, Wang J . A potent fluorescent ATP-like inhibitor of cAMP-dependent protein kinase. J Biol Chem. 1989; 264(14):7989-93. View

10.

Demetri G, von Mehren M, Blanke C, Van Den Abbeele A, Eisenberg B, Roberts P . Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002; 347(7):472-80. DOI: 10.1056/NEJMoa020461. View

11.

Zhang H, Kazazic S, Schaub T, Tipton J, Emmett M, Marshall A . Enhanced digestion efficiency, peptide ionization efficiency, and sequence resolution for protein hydrogen/deuterium exchange monitored by Fourier transform ion cyclotron resonance mass spectrometry. Anal Chem. 2009; 80(23):9034-41. PMC: 2784605. DOI: 10.1021/ac801417d. View

12.

Schindler T, Bornmann W, Pellicena P, Miller W, Clarkson B, Kuriyan J . Structural mechanism for STI-571 inhibition of abelson tyrosine kinase. Science. 2000; 289(5486):1938-42. DOI: 10.1126/science.289.5486.1938. View

13.

Verweij J, Casali P, Zalcberg J, Lecesne A, Reichardt P, Blay J . Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet. 2004; 364(9440):1127-34. DOI: 10.1016/S0140-6736(04)17098-0. View

14.

Yun C, Mengwasser K, Toms A, Woo M, Greulich H, Wong K . The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci U S A. 2008; 105(6):2070-5. PMC: 2538882. DOI: 10.1073/pnas.0709662105. View

15.

Tarn C, Merkel E, Canutescu A, Shen W, Skorobogatko Y, Heslin M . Analysis of KIT mutations in sporadic and familial gastrointestinal stromal tumors: therapeutic implications through protein modeling. Clin Cancer Res. 2005; 11(10):3668-77. DOI: 10.1158/1078-0432.CCR-04-2515. View

16.

Heinrich M, Corless C, Demetri G, Blanke C, von Mehren M, Joensuu H . Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003; 21(23):4342-9. DOI: 10.1200/JCO.2003.04.190. View

17.

Morrison J . Kinetics of the reversible inhibition of enzyme-catalysed reactions by tight-binding inhibitors. Biochim Biophys Acta. 1969; 185(2):269-86. DOI: 10.1016/0005-2744(69)90420-3. View

18.

Zhang Z, Li W, Logan T, Li M, G Marshall A . Human recombinant [C22A] FK506-binding protein amide hydrogen exchange rates from mass spectrometry match and extend those from NMR. Protein Sci. 1997; 6(10):2203-17. PMC: 2143553. DOI: 10.1002/pro.5560061015. View

19.

Godin-Heymann N, Ulkus L, Brannigan B, McDermott U, Lamb J, Maheswaran S . The T790M "gatekeeper" mutation in EGFR mediates resistance to low concentrations of an irreversible EGFR inhibitor. Mol Cancer Ther. 2008; 7(4):874-9. DOI: 10.1158/1535-7163.MCT-07-2387. View

20.

Zhang H, Bou-Assaf G, Emmett M, Marshall A . Fast reversed-phase liquid chromatography to reduce back exchange and increase throughput in H/D exchange monitored by FT-ICR mass spectrometry. J Am Soc Mass Spectrom. 2008; 20(3):520-4. PMC: 2673454. DOI: 10.1016/j.jasms.2008.11.010. View