Mechanisms of resistance to imatinib mesylate in gastrointestinal stromal tumors and activity of the PKC412 inhibitor against imatinib-resistant mutants

Dębiec‐Rychter, Maria; Cools, Jan; Dumez, Herlinde; Sciot, Raf; Stul, Michel; Mentens, Nele; Vranckx, Hilde; Wasąg, Bartosz; Prenen, Hans; Roesel, Johannes; Hagemeijer, Anne; Oosterom, Allan Van; Marynen, Peter

doi:10.1053/j.gastro.2004.11.020

Cited by 453 publications

(322 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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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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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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“…It is now established that acquired mutations in KIT or PDGFRA account for most secondary resistance, and that these mutations occur almost exclusively in the same gene and allele as the primary oncogenic driver mutation. 35,[134][135][136][137][138][139][140] In a phase II imatinib study for advanced GIST, 67% of the patients whose tumor showed imatinib resistance had a new, or secondary, mutation in KIT. Notably, these mutations were common among tumors with a primary exon 11 mutation, but were not observed in wild-type GIST samples.…”

Section: Secondary Resistancementioning

confidence: 99%

“…Drug resistance has also been observed in PDGFRAmutant GISTs, in which the most common one is an acquired D842V mutation (activation loop). 135,137 Additional studies using more sensitive assays have identified secondary mutations in 480% of drug-resistant GIST lesions. [141][142][143] More sobering is that there is significant heterogeneity of resistance across different lesions, and even within different areas of the same lesion.…”

Section: Secondary Resistancementioning

confidence: 99%

Gastrointestinal stromal tumors: what do we know now?

2014

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Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the GI tract, arising from the interstitial cells of Cajal, primarily in the stomach and small intestine. They manifest a wide range of morphologies, from spindle cell to epithelioid, but are immunopositive for KIT (CD117) and/or DOG1 in essentially all cases. Although most tumors are localized at presentation, up to half will recur in the abdomen or spread to the liver. The growth of most GISTs is driven by oncogenic mutations in either of two receptor tyrosine kinases: KIT (75% of cases) or PDGFRA (10%). Treatment with tyrosine kinase inhibitors (TKIs) such as imatinib, sunitinib, and regorafenib is effective in controlling unresectable disease; however, drug resistance caused by secondary KIT or PDGFRA mutations eventually develops in 90% of cases. Adjuvant therapy with imatinib is commonly used to reduce the likelihood of disease recurrence after primary surgery, and for this reason assessing the prognosis of newly resected tumors is one of the most important roles for pathologists. Approximately 15% of GISTs are negative for mutations in KIT and PDGFRA. Recent studies of these so-called wild-type GISTs have uncovered a number of other oncogenic drivers, including mutations in neurofibromatosis type I, RAS genes, BRAF, and subunits of the succinate dehydrogenase complex. Routine genotyping is strongly recommended for optimal management of GISTs, as the type and dose of TKI used for treatment is dependent on the mutation identified.

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Mechanisms of resistance to imatinib mesylate in gastrointestinal stromal tumors and activity of the PKC412 inhibitor against imatinib-resistant mutants

Cited by 453 publications

References 23 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

Gastrointestinal stromal tumors: what do we know now?

Tyrosine Kinase Inhibitors

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