KIT Mutations in GIST

Current Opinion in Genetics and Development

Volumn 17, Issue 1, 2007, Pages 3-7

  Fletcher, Jonathan A ^a   Rubin, Brian P ^b  

^a BRIGHAM AND WOMEN S HOSPITAL   (United States)

^b TAUSSIG CANCER INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

EVEROLIMUS; FLAVOPIRIDOL; HEAT SHOCK PROTEIN 90 INHIBITOR; IMATINIB; PLATELET DERIVED GROWTH FACTOR ALPHA RECEPTOR; STEM CELL FACTOR; SUNITINIB;

CLINICAL FEATURE; ENZYME ACTIVATION; ENZYME DEGRADATION; ENZYME INHIBITION; GASTROINTESTINAL TUMOR; GENE MUTATION; GENE TARGETING; GENETIC TRANSCRIPTION; HUMAN; NONHUMAN; ONCOGENE; PRIORITY JOURNAL; REVIEW; STANDARDIZATION;

ANTINEOPLASTIC AGENTS; DRUG RESISTANCE, NEOPLASM; GASTROINTESTINAL STROMAL TUMORS; HSP90 HEAT-SHOCK PROTEINS; HUMANS; INDOLES; MODELS, BIOLOGICAL; MUTATION; PIPERAZINES; PROTEIN KINASE INHIBITORS; PROTO-ONCOGENE PROTEINS C-KIT; PYRIMIDINES; PYRROLES; RECEPTOR, PLATELET-DERIVED GROWTH FACTOR ALPHA; SIGNAL TRANSDUCTION;

EID: 33846262582     PISSN: 0959437X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.gde.2006.12.010     Document Type: Review

References (33)

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6. Heinrich M.C., Corless C.L., Blanke C.D., Demetri G.D., Joensuu H., Roberts P.J., Eisenberg B.L., von M.M., Fletcher C.D., Sandau K., et al. Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol 24 (2006) 4764-4774. Secondary kinase-domain KIT mutations are rare in GISTs with primary resistance to imatinib therapy but are found in 67% of GISTs that progress on imatinib after an initial clinical response. GISTs progressing on imatinib therapy remain KIT-dependent, as shown by KIT RNAi knockdown studies.
7. Debiec-Rychter M., Cools J., Dumez H., Sciot R., Stul M., Mentens N., Vranckx H., Wasag B., Prenen H., Roesel J., et al. Mechanisms of resistance to imatinib mesylate in gastrointestinal stromal tumors and activity of the PKC412 inhibitor against imatinib-resistant mutants. Gastroenterology 128 (2005) 270-279. The authors demonstrate that the staurostorine analog PKC412 is an effective inhibitor of KIT V654A and T670I oncogenic mutations, which are frequent mechanisms of secondary imatinib-resistance in GISTs. Likewise, PKC412 inhibited the PDGFRA D842V oncoprotein, which is a mechanism of primary imatinib-resistance in GIST.
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9. Demetri G.D., George S., Heinrich M.C., Fletcher J.A., Fletcher C.D.M., Desai J., Cohen D.P., Scigalla P., Cherrington J.M., and Van den Abbeele A.D. Clinical activity and tolerability of the multi-targeted tyrosine kinase inhibitor SU11248 in patients (pts) with metastatic gastrointestinal stromal tumor (GIST) refractory to imatinib mesylate. Proc Am Soc Clin Oncol 22 (2003) 814
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12. Li F.P., Fletcher J.A., Heinrich M.C., Garber J.E., Sallan S.E., Curiel-Lewandrowski C., Duensing A., van de R.M., Schnipper L.E., and Demetri G.D. Familial gastrointestinal stromal tumor syndrome: phenotypic and molecular features in a kindred. J Clin Oncol 23 (2005) 2735-2743
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14. Hartmann K., Wardelmann E., Ma Y., Merkelbach-Bruse S., Preussner L.M., Woolery C., Baldus S.E., Heinicke T., Thiele J., Buettner R., et al. Novel germline mutation of KIT associated with familial gastrointestinal stromal tumors and mastocytosis. Gastroenterology 129 (2005) 1042-1046
15. Tarn C., Merkel E., Canutescu A.A., Shen W., Skorobogatko Y., Heslin M.J., Eisenberg B., Birbe R., Patchefsky A., Dunbrack R., et al. Analysis of KIT mutations in sporadic and familial gastrointestinal stromal tumors: therapeutic implications through protein modeling. Clin Cancer Res 11 (2005) 3668-3677. Mutations were mapped in several GISTs, including a case of familial GIST using protein modeling based on existing crystal structures. Mapping of the mutations showed that mutations within the juxtamembrane domain and exon 13 K642E act to destabilize the autoinhibited conformation of KIT without altering the nucleotide binding domain. Thus, as is seen clinically, patients harboring GISTs with juxtamembrane domain mutations involving exon 11 of KIT would be expected to respond to imatinib.
16. Chen L.L., Trent J.C., Wu E.F., Fuller G.N., Ramdas L., Zhang W., Raymond A.K., Prieto V.G., Oyedeji C.O., Hunt K.K., et al. A missense mutation in KIT kinase domain 1 correlates with imatinib resistance in gastrointestinal stromal tumors. Cancer Res 64 (2004) 5913-5919
17. Antonescu C.R., Besmer P., Guo T., Arkun K., Hom G., Koryotowski B., Leversha M.A., Jeffrey P.D., Desantis D., Singer S., et al. Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res 11 (2005) 4182-4190. The authors demonstrate KIT secondary kinase domain mutations, generally located in exon 17, in 7 of 15 patients (46%) showing acquired resistance to imatinib after an initial clinical response. By contrast, KIT kinase domain mutations were not found in patients with primary imatinib-resistance (N = 3) or in those responding to imatinib (N = 13).
18. Bauer S., Yu L.K., Demetri G.D., and Fletcher J.A. Heat shock protein 90 inhibition in imatinib-resistant gastrointestinal stromal tumor. Cancer Res 66 (2006) 9153-9161. The authors report preclinical studies in GIST cell lines showing that HSP90 inhibition by 17-AAG results in degradation of KIT oncoproteins containing imatinib-resistant secondary kinase domain mutations, and resulting in GIST cell proliferation arrest and apoptosis. These studies show that HSP90 inhibition might be an effective salvage strategy in patients with imatinib-resistant GIST.
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20. Duensing A., Medeiros F., McConarty B., Joseph N.E., Panigrahy D., Singer S., Fletcher C.D., Demetri G.D., and Fletcher J.A. Mechanisms of oncogenic KIT signal transduction in primary gastrointestinal stromal tumors (GISTs). Oncogene 23 (2004) 3999-4006
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22. Rossi F., Ehlers I., Agosti V., Socci N.D., Viale A., Sommer G., Yozgat Y., Manova K., Antonescu C.R., and Besmer P. Oncogenic Kit signaling and therapeutic intervention in a mouse model of gastrointestinal stromal tumor. Proc Natl Acad Sci USA 103 (2006) 12843-12848. Using a transgenic knock-in mouse model resulting in germline activation of a Kit V558Δ allele, the authors studied Kit signaling before and after administration of imatinib or RAD001 (everolimus), an mTOR inhibitor. Treatment with imatinib resulted in decreased PI3K and mTOR signaling as well as changes in the expression pattern of IFN-inducible genes and genes involved in cell cycle regulation. Treatment with RAD001 resulted in a decrease in the translational response and cell proliferation, suggesting that RAD001 might be effective in the treatment of GIST.
23. Tarn C., Skorobogatko Y.V., Taguchi T., Eisenberg B., von M.M., and Godwin A.K. Therapeutic effect of imatinib in gastrointestinal stromal tumors: AKT signaling dependent and independent mechanisms. Cancer Res 66 (2006) 5477-5486. The authors used lentiviral vectors to express constitutively active AKT1 or AKT2 in human GIST cell lines to define AKT-dependent and -independent functions of KIT signal transduction. They found that AKT1 or AKT2 was able to rescue imatinib-blocked glucose transport but not apoptosis.
24. 18 fluoro-deoxyglucose PET imaging of xenografts of the murine hematopoietic cell line FDC-P1, carrying different KIT imatinib sensitive or resistant mutants. This tool might be useful in screening various new pharmacologic inhibitors on a variety of different KIT mutation backgrounds.
25. Trent J.C., Ramdas L., Dupart J., Hunt K., Macapinlac H., Taylor E., Hu L., Salvado A., Abbruzzese J.L., Pollock R., et al. Early effects of imatinib mesylate on the expression of insulin-like growth factor binding protein-3 and positron emission tomography in patients with gastrointestinal stromal tumor. Cancer 107 (2006) 1898-1908. Insulin-like growth factor binding protein-3 (IGFBP3) was identified by gene expression analysis of the human GIST882 cell line pre- and post-imatinib as being upregulated in response to imatinib, and this was confirmed in primary human tumor samples before and after administration of imatinib. The authors suggest that IFFBP3 levels might represent an early marker of therapeutic response in GIST.
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28. Prenen H., Cools J., Mentens N., Folens C., Sciot R., Schoffski P., van O.A., Marynen P., and biec-Rychter M. Efficacy of the kinase inhibitor SU11248 against gastrointestinal stromal tumor mutants refractory to imatinib mesylate. Clin Cancer Res 12 (2006) 2622-2627. The authors show that the multikinase inhibitor sunitinib (SU11248) is an effective inhibitor of GISTs expressing KIT oncoproteins with imatinib-resistant V654A and T670I mutations. However, sunitinib did not inhibit a GIST expressing the imatinib-resistant PDGFRA D842V mutation. These studies underscore the role of sunitinib (recently FDA-approved) against a subset of the KIT kinase domain secondary mutations found in patients with imatinib-resistant GIST.
29. Sommer G., Agosti V., Ehlers I., Rossi F., Corbacioglu S., Farkas J., Moore M., Manova K., Antonescu C.R., and Besmer P. Gastrointestinal stromal tumors in a mouse model by targeted mutation of the Kit receptor tyrosine kinase. Proc Natl Acad Sci USA 100 (2003) 6706-6711
30. Rubin B.P., Antonescu C.R., Scott-Browne J.P., Comstock M.L., Gu Y., Tanas M.R., Ware C.B., and Woodell J. A knock-in mouse model of gastrointestinal stromal tumor harboring kit K641E. Cancer Res 65 (2005) 6631-6639. The authors describe a transgenic knock-in murine GIST model harboring a germline KIT K641E mutation. The model is based on the finding of this mutation in both sporadic and familial GIST. Notably, homozygous as well as heterozygous KIT K641E mice are viable and develop GISTs and/or interstitial cell of Cajal hyperplasia with 100% penetrance and in a dose-dependent manner. This mouse model appears to faithfully recapitulate the salient findings of familial GIST.
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