A Missense Mutation in KIT Kinase Domain 1 Correlates with Imatinib Resistance in Gastrointestinal Stromal Tumors

Chen, Lei L.; Trent, Jonathan C.; Wu, Elsie F.; Fuller, Gregory N.; Ramdas, Latha; Zhang, Wei; Raymond, A. Kevin; Prieto, Víctor G.; Oyedeji, Caroline O.; Hunt, Kelly K.; Pollock, Raphael E.; Feig, Barry W.; Hayes, Kimberly; Choi, Haesun; Macapinlac, Homer A.; Hittelman, Walter N.; Velasco, Marco A. De; Patel, Shreyaskumar; Burgess, M. A.; Benjamin, Robert S.; Frazier, Marsha L.

doi:10.1158/0008-5472.can-04-0085

Cited by 322 publications

(221 citation statements)

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“…Another intriguing aspect that is becoming evident also in the literature (Chen et al, 2004;Tamborini et al, 2004Tamborini et al, , 2005Debiec-Rychter et al, 2005;Antonescu et al, 2005;Wardelmann et al, 2005) is why these mutations, T670I and V654A, are detected only in GIST patients who underwent imatinib treatment, whereas others, D820Y and N822K, are not (Debiec-Rychter et al, 2005). Most likely, the frequency of these mutations is very low and only the selective pressure of the drug is able to make evident the resistant clones.…”

Section: Molecular Modelingmentioning

confidence: 95%

“…Recently, GIST cases showing acquired resistance to imatinib, that is, tumoral growth after an initial response, have been reported and molecularly analysed (Chen et al, 2004;Tamborini et al, 2004Tamborini et al, , 2005Antonescu et al, 2005;Debiec-Rychter et al, 2005;Wardelmann et al, 2005). Although several mechanisms have been proposed to be responsible for this phenomenon, including KIT gene amplification, the emergence of additional point mutations appears to be the most frequent event.…”

mentioning

confidence: 99%

“…The secondary point mutations till now described always involve the kinase domain of the receptor and have been described in exons 13, 14 and 17 of c-Kit gene and in exon 18 of PDGFRA gene (Chen et al, 2004;Tamborini et al, 2004Tamborini et al, , 2005Antonescu et al, 2005;Debiec-Rychter et al, 2005;Wardelmann et al, 2005). Their presence in the ATP pocket of the kinase suggests that imatinib is not able to inhibit the receptor efficiently, most likely because of a different tridimensional proteic structure of the ATP pocket induced by these additional mutations.…”

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confidence: 99%

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Functional analyses and molecular modeling of two c-Kit mutations responsible for imatinib secondary resistance in GIST patients

et al. 2006

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Imatinib-acquired resistance related to the presence of secondary point mutations has become a frequent event in gastrointestinal stromal tumors. Here, transient transfection experiments with plasmids carrying two different KIT-acquired point mutations were performed along with immunoprecipitation of total protein extracts, derived from imatinib-treated and untreated cells. The molecular mechanics/Poisson Boltzmann surface area computational techniques were applied to study the interactions of the wild-type and mutated receptors with imatinib at the molecular level. Biochemical analyses showed KIT phosphorylation in cells transfected with vectors carrying the specific mutant genes. Imatinib treatment demonstrated that T670I was insensitive to the drug at all the applied concentrations, whereas V654A was inhibited by 6 lM of imatinib. The modeling of the mutated receptors revealed that both substitutions affect imatinib-binding site, but to a different extent: T670I substantially modifies the binding pocket, whereas V654A induces only relatively confined structural changes. We demonstrated that T670I and V654A cause indeed imatinib-acquired resistance and that the former is more resistant to imatinib than the latter. The application of molecular simulations allowed us to quantify the interactions between the mutated receptors and imatinib, and to propose a molecular rationale for this type of drug resistance.

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Section: Molecular Modelingmentioning

confidence: 95%

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confidence: 99%

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confidence: 99%

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Functional analyses and molecular modeling of two c-Kit mutations responsible for imatinib secondary resistance in GIST patients

et al. 2006

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“…The crystal structures of the WT tyrosine kinase domain of Kit bound to IM (PDB: 1T46) (Mol et al, 2004) and ATP (PDB: 1PKG) (Mol et al, 2003) were utilized as templates for homology modeling of the Val654Ala mutation (Chen et al, 2004). Interactive docking studies were conducted (FlexX, Tripos Inc., St Louis, MO, USA) to correlate any structural changes before and after introducing the mutation.…”

Section: Homology Modeling and Interactive Dockingmentioning

confidence: 99%

“…Five potential resistance mechanisms are: functional resistance (exon 9 and WT KIT); genomic amplification and KIT overexpression (Bauer et al, 2005); acquisition of secondary mutations (e.g. V654A) (Chen et al, 2004); activation of alternate RTKs (Mahadevan et al, 2005a); and ATP-dependent IM efflux through ABCB1/ABCC1 transporters (Theou et al, 2005). Our strategy was to develop an IM-resistant GIST cell line and perform gene expression profiling (GEP) on GIST-S and GIST-R cells to identify marker(s) of IM resistance.…”

Section: Introductionmentioning

confidence: 99%

A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors

et al. 2007

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KIT or a-platelet-derived growth factor receptor (a-PDGFR) activating mutations are the pathogenic mechanisms that characterize gastrointestinal stromal tumors (GIST). Despite excellent responses to imatinib mesylate (IM), patients are relapsing. We developed an IM-resistant GIST cell line (GIST-R) from the IMsensitive GIST882 cell line (GIST-S) by growing these cells in IM. Gene expression profiling (GEP) of GIST-S, GIST-R cells and two IM resistant GIST patients demonstrated that KIT is downregulated implying a major role in IM resistance. Instead, GIST-R cells have acquired IM resistance by overexpressing the oncogenic receptor tyrosine kinase -AXL -in a 'kinase switch'. Further, the two IM resistant GIST patients express AXL and not c-Kit, seen by immunohistochemistry (IHC). Real time reverse transcriptase-polymerase chain reaction and Western blotting of the GIST-S and GIST-R cells confirmed the switch from Kit to AXL. In GIST-R, AXL is tyrosine phosphorylated and its ligand growtharrest-specific gene 6 is overexpressed implying autocrine activation. The kinase switch is associated with a morphological change from spindle to epithelioid. Molecular modeling of the kinase domain of mutant c-Kit (V654A) and AXL showed no binding to IM but efficient binding to MP470, a novel c-Kit/AXL kinase inhibitor. MP470 synergizes with docetaxel (taxotere) and is cytotoxic to GIST cells.

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KIT as a Therapeutic Target in Metastatic Melanoma

Carvajal

Antonescu²,

Wolchok³

et al. 2011

JAMA

782

524

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Context Some melanomas arising from acral, mucosal, and chronically sun-damaged sites harbor activating mutations and amplification of the type III transmembrane receptor tyrosine kinase KIT. We explored the effects of KIT inhibition using imatinib mesylate in this molecular subset of disease. Objective To assess clinical effects of imatinib mesylate in patients with melanoma harboring KIT alterations. Design, Setting, and Patients A single-group, open-label, phase 2 trial at 1 community and 5 academic oncology centers in the United States of 295 patients with melanoma screened for the presence of KIT mutations and amplification between April 23, 2007, and April 16, 2010. A total of 51 cases with such alterations were identified and 28 of these patients were treated who had advanced unresectable melanoma arising from acral, mucosal, and chronically sun-damaged sites. Intervention Imatinib mesylate, 400 mg orally twice daily. Main Outcome Measures Radiographic response, with secondary end points including time to progression, overall survival, and correlation of molecular alterations and clinical response. Results Two complete responses lasting 94 (ongoing) and 95 weeks, 2 durable partial responses lasting 53 and 89 (ongoing) weeks, and 2 transient partial responses lasting 12 and 18 weeks among the 25 evaluable patients were observed. The overall durable response rate was 16% (95% confidence interval [CI], 2%–30%), with a median time to progression of 12 weeks (interquartile range [IQR], 6–18 weeks; 95% CI, 11–18 weeks), and a median overall survival of 46.3 weeks (IQR, 28 weeks-not achieved; 95% CI, 28 weeks-not achieved). Response rate was better in cases with mutations affecting recurrent hotspots or with a mutant to wild-type allelic ratio of more than 1 (40% vs 0%, P=.05), indicating positive selection for the mutated allele. Conclusions Among patients with advanced melanoma harboring KIT alterations, treatment with imatinib mesylate results in significant clinical responses in a subset of patients. Responses may be limited to tumors harboring KIT alterations of proven functional relevance.

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A Missense Mutation in KIT Kinase Domain 1 Correlates with Imatinib Resistance in Gastrointestinal Stromal Tumors

Cited by 322 publications

References 19 publications

Functional analyses and molecular modeling of two c-Kit mutations responsible for imatinib secondary resistance in GIST patients

Functional analyses and molecular modeling of two c-Kit mutations responsible for imatinib secondary resistance in GIST patients

A novel tyrosine kinase switch is a mechanism of imatinib resistance in gastrointestinal stromal tumors

KIT as a Therapeutic Target in Metastatic Melanoma

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