Abstract
KIT is a type III receptor tyrosine kinase encoded by a gene locus on the long arm of chromosome 4. It is closely related to Fms-like tyrosine kinase 3 (FLT3), platelet-derived growth factor receptor alpha and beta (PDGFRα, PDGFRβ), and colony-stimulating factor 1 receptor (CSF1R). Depending on its degree of glycosylation, the molecular mass of KIT is 140–160 kD. KIT is normally expressed on the surface of hematopoietic stem and progenitor cells, mast cells, melanocytes, germ cells, and interstitial cells of Cajal. There are both transmembrane and soluble forms of KIT; however, the transmembrane form is believed to be biologically active, while the role of soluble KIT is poorly understood. The ligand for KIT is stem cell factor (SCF), also known as steel factor or mast cell growth factor. Both soluble and membrane-bound forms of SCF exist, resulting from alternative splicing of exon 6 (Broudy, Blood 90:1345–1364, 1997; Heinrich et al., J Clin Oncol 20:1692–1703, 2002; Lennartsson and Ronnstrand, Curr Cancer Drug Targets 6:65–75, 2006).
Access provided by CONRICYT-eBooks. Download reference work entry PDF
Similar content being viewed by others
Keywords
- ABL
- BCR-ABL
- JAK/STAT
- KIT
- MAP kinase
- MetaGIST study
- PI3-K
- Platelet-derived growth factor receptor alpha (PDGFRα)
- Platelet-derived growth factor receptor alpha (PDGFRα)
- Stem cell factor (SCF)
Target: KIT (Formerly c-Kit)
KIT is a type III receptor tyrosine kinase encoded by a gene locus on the long arm of chromosome 4. It is closely related to Fms-like tyrosine kinase 3 (FLT3), platelet-derived growth factor receptor alpha and beta (PDGFRα, PDGFRβ) , and colony-stimulating factor 1 receptor (CSF1R). Depending on its degree of glycosylation, the molecular mass of KIT is 140–160 kD. KIT is normally expressed on the surface of hematopoietic stem and progenitor cells, mast cells, melanocytes, germ cells, and interstitial cells of Cajal. There are both transmembrane and soluble forms of KIT; however, the transmembrane form is believed to be biologically active, while the role of soluble KIT is poorly understood. The ligand for KIT is stem cell factor (SCF) , also known as steel factor or mast cell growth factor. Both soluble and membrane-bound forms of SCF exist, resulting from alternative splicing of exon 6 (Broudy 1997; Heinrich et al. 2002; Lennartsson and Ronnstrand 2006).
Biology of the Target
KIT is critical for hematopoiesis, the development and migration of melanocytes, the development of the gonads, gut peristalsis, and the survival and function of mast cells. In mice, KIT is the gene product of the white spotting locus (W), and SCF is encoded by the steel locus (Sl). It was observed that loss of function mutations at these two locations results in similar phenotypes – bone marrow failure/anemia, white spotting of the fur, loss of mast cells, abnormal peristalsis (decrease in the interstitial cell of Cajal), and sterility. Complete or near-complete loss of KIT expression is embryonic lethal. These observations prompted studies which suggested that SCF is the cognate ligand of KIT (Dexter and Moore 1977).
KIT becomes activated when stem cell factor (SCF) binds to the KIT extracellular domain. SCF is expressed by cells that make up the microenvironment of KIT-expressing cells including epithelial cells, endothelial cells, fibroblasts, Sertoli cells, etc. Binding of SCF leads to receptor dimerization, kinase activation, KIT autophosphorylation, and activation of downstream signaling pathways including the PI3-K , MAP kinase , and JAK/STAT pathways. Signaling via KIT promotes cell growth, survival, and proliferation. However, certain mutations in KIT lead to its constitutive activation in the absence of SCF. These activating mutations have been linked to acute myeloid leukemia (AML), mast cell tumors, melanoma, seminoma, and gastrointestinal stromal tumors (GIST) (Lennartsson and Ronnstrand 2006; Lennartsson et al. 2005).
Activating KIT mutations can be located in the intracellular or extracellular domains . Extracellular mutations are typically located in exons 8 and 9. KIT exon 8 mutations are associated with AML, and these mutations are believed to induce hypersensitivity to SCF, rather than constitutive activation in the absence of SCF. Exon 9 mutations are found in approximately 10% of GIST patients. The activation mechanism of these mutations is being investigated and may be related to KIT dimerization or conformational changes; however, these mutations do cause constitutive activation in the absence of SCF. Intracellular mutations are most commonly associated with exons 11 and 17. Mutations in exon 11 are found in approximately 70% of GIST patients. These mutations occur in the juxtamembrane domain and prevent this autoinhibitory region from locking the kinase in “off” position in the absence of SCF . D816V, a mutation in exon 17, is associated with mast cell neoplasms, leukemia, and seminoma. This mutation is located in the activation loop and stabilizes the kinase activation loop in the active conformation, promoting spontaneous kinase activity.
Target Assessment
KIT protein expression is readily assessed in fixed tissue using immunohistochemistry (fixed tissue) or flow cytometry (blood, bone marrow) (Craig and Foon 2008; Turner and Goldsmith 2009; Miettinen and Lasota 2005; Rubin and Heinrich 2015). As noted below, measurement of KIT expression has some diagnostic utility. More importantly, detection of the presence or absence of KIT mutations is predictive of response of GIST, melanoma, and mast cell neoplasms to KIT kinase inhibitors.
Role of the Target in Cancer
Rank: 10
High-Level Overview
A number of KIT kinase inhibitors have been approved by the FDA. Three of these inhibitors, imatinib, sunitinib, and regorafenib, have specific FDA-approved indications for treatment of GIST (Blay 2010; Overton and Heinrich 2014). In addition, imatinib is FDA approved for treatment of adult patients with aggressive systemic mastocytosis without the D816V KIT mutation or with unknown KIT mutational status (Piccaluga et al. 2007). Multiple phase 2 trials have shown efficacy of imatinib and nilotinib in KIT-mutant melanoma, though no KIT inhibitors have been FDA approved for treatment of this disease (Hodi et al. 2013; Guo et al. 2011; Carvajal et al. 2011, 2015; Lee et al. 2015a).
Diagnostic, Prognostic, and Predictive
Over the past decade, immunohistochemistry for detection of KIT protein (CD117 antigen) has helped standardize the diagnosis of GIST (Rubin and Heinrich 2015). GIST is the most common spindle cell neoplasm (sarcoma) of the GI tract, but morphologically it can be difficult or impossible to distinguish from smooth muscle tumors, schwannomas, desmoids tumors (aggressive fibromatosis), and metastatic melanoma. Indeed, until the application of KIT immunohistochemistry to the pathologic classification of these lesions, GIST was not even recognized as a separate pathologic entity and these tumors were classified as either benign or malignant smooth muscle tumors (Turner and Goldsmith 2009; Miettinen and Lasota 2005). As noted below, the use of KIT kinase inhibitors has revolutionized the treatment of GIST – making the accurate diagnosis of GIST even more critical. KIT immunohistochemistry can also be used in the diagnosis of melanoma, AML, mast cell neoplasms, and germ cell tumors (Turner and Goldsmith 2009). In addition, KIT is a useful marker for flow cytometric identification of bone marrow blast cells and classification of cases of myelodysplastic syndrome and AML (Craig and Foon 2008).
The presence and type of KIT mutation found in primary GIST has been shown to have prognostic value in retrospective population studies (Andersson et al. 2006; Hou et al. 2009). Similar results have been shown in the placebo arm of a double blind, randomized study of placebo versus 1 year of adjuvant imatinib following curative intent resection of primary GIST. Notably, the presence of a KIT exon 11 in frame deletion mutation was associated with a much higher risk of recurrence than seen in tumors with other KIT genotypes (HR 3.45, p = 0.024 compared with wild-type tumors) (Turner and Goldsmith 2009; Miettinen and Lasota 2005; Corless et al. 2010). KIT mutation status also influences the effectiveness of adjuvant imatinib given after curative intent surgery, with patients whose GIST harbor KIT exon 11 mutations deriving the greatest benefit from 3 years of adjuvant imatinib compared with 1 year of adjuvant imatinib (Joensuu et al. 2016). KIT mutation data is now being incorporated into risk stratification algorithms to help predict the risk of recurrence after surgery and to help guide decision making concerning the use of adjuvant imatinib in GIST (Joensuu et al. 2015).
Translational studies utilizing tumor samples from large clinical studies have identified tumor genotype as a strong predictor of clinical benefit for patients with metastatic GIST treated with imatinib. Specifically, patients with KIT exon 11-mutant GIST (approximately 70% of GIST) have the highest rates of objective response, progression-free survival (PFS), and overall survival (OS) compared with patients whose tumors had no kinase mutations (wild-type GIST, approximately 10–15% of GIST) or GIST with somatic KIT exon 9 mutations (~10% of patients). In this SWOG/NCIC study, PFS was 24.7 months for KIT exon 11-mutant tumors versus 16.7 months for wild-type GIST and 12.8 months for patient with KIT exon 9-mutant tumors. In terms of the effect on overall survival, KIT exon 11-mutant GIST patients had a median OS of 60 months versus 38.4 months for wild-type GIST patients and 49 months for KIT exon 9-mutant GIST patients (Heinrich et al. 2003, 2008a; Debiec-Rychter et al. 2004, 2006).
The effect of tumor genotype and imatinib dose on clinical outcomes was also analyzed in the MetaGIST study (400 versus 800 mg dosing for metastatic GIST). Within patients with KIT exon 9-mutant GIST, PFS was significantly longer for patients treated with the high-dose arm (P = 0.017). For patients whose tumor had genotypes other than KIT exon 9 mutation, no difference in clinical outcomes was observed between treatment arms. In terms of OS, there was a trend toward a survival advantage for patients with KIT exon 9-mutant GIST treated with high-dose therapy (p = 0.15) (2010). Tumor genotyping is recommended in oncology professional guidelines to help optimize care of patients with newly diagnosed metastatic GIST (von Mehren et al. 2012, 2014). In addition, KIT mutation status has recently been incorporated into a prognostic nomogram for patient with metastatic GIST treated with first-line imatinib (Lee et al. 2015b).
Besides its impact on response to imatinib, KIT mutation status also influences clinical outcome in patients treated with sunitinib as second-line therapy for metastatic GIST. In contrast to the experience with first-line imatinib, patients with KIT exon 9-mutant or wild-type GIST are predicted to have better outcomes with sunitinib treatment compared with patients with KIT exon 11-mutant GIST (Heinrich et al. 2008b; Reichardt et al. 2016).
Therapeutics
To date, all of the FDA-approved anti-KIT therapeutics are small molecule tyrosine kinase inhibitors. Currently, there are numerous agents with KIT inhibitory activity that are FDA approved for treatment of one or more human malignancies, including imatinib, sunitinib, regorafenib, nilotinib, dasatinib, sorafenib, pazopanib, and ponatinib. However, only imatinib (GIST, mastocytosis), sunitinib (GIST), and regorafenib (GIST) are FDA approved for treatment of KIT-mutant disease.
Preclinical Summary
A large body of evidence has established KIT as therapeutic target, and subsequent research has studied the efficacy of various tyrosine kinase inhibitors in blocking its activity in vivo and in vitro. Research in 2000 by Ma et al. showed efficacy of a small group of indolinones against KIT (Ma et al. 2000). They also reinforced a direct link between KIT function and mast cell survival. In the same year, Heinrich et al. and Buchdunger et al. investigated the use of imatinib (formerly STI-571) as a KIT inhibitor. Imatinib was found to selectively inhibit KIT tyrosine kinase activity as well as inhibit the activation of downstream effector proteins. They also found that imatinib was more potent against certain activating KIT mutations than against WT KIT and concluded that the clinical profile of imatinib should be expanded to include KIT (in addition to its known targets: ABL , BCR-ABL , and PDGFRA and PDGFRB) (Buchdunger et al. 2000; Heinrich et al. 2000).
In this same time frame, Tuveson et al. developed a GIST tumor cell line – GIST882 – harboring an activating mutation in the KIT tyrosine kinase I domain. Incubation of this cell line with imatinib led to decreased proliferation and increased apoptosis supporting a role of KIT in GIST pathology and the therapeutic potential for imatinib in GIST patients (Tuveson et al. 2001). Later, in 2003, Abrams et al. evaluated the activity of sunitinib (formerly SU11248) against KIT in a small cell lung cancer model (Abrams et al. 2003). Treatment with sunitinib inhibited KIT tyrosine phosphorylation and cellular proliferation. The results of this study suggested a clinical potential for sunitinib in the treatment of tumors with activating KIT mutations.
KIT mutations are found in the vast majority of human mast cell neoplasms. In particular, the KIT D816V mutation is found in >90% of cases. Pre-clinical studies of mastocystosis cell lines and/or patient samples have shown that KIT inhibition by kinase inhibitors reduces proliferation and induces apoptosis of cells. Unfortunately, the D816V mutation is resistant to most of the available kinase inhibitors. However, these studies do indicate that KIT is a compelling target in mastocytosis and have spurred efforts to develop inhibitors with activity against the D816V mutation (Gotlib et al. 2005; Schittenhelm et al. 2006; Shah et al. 2006).
More recently, KIT mutations have been found in a subset of human melanoma. In particular, these mutations are more common in acral or mucosal melanomas. In vitro studies of KIT-mutant melanoma cell lines have demonstrated that KIT inhibitors can exert an anti-proliferative and pro-apoptotic effect on these cells (Beadling et al. 2008; Jiang et al. 2008).
All of these studies and many more have established KIT as a therapeutic target in cancers driven by the hyperactivation of KIT and demonstrated the efficacy of specific tyrosine kinase inhibitors in controlling cell growth resulting from KIT hyperactivity.
Clinical Summary
Prior to 2000, there was no active medical treatment for metastatic GIST (DeMatteo et al. 2002). However, the introduction of small molecule tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of GIST. Currently, there are three FDA-approved treatments for advanced GIST: imatinib for front-line treatment, sunitinib for second-line treatment, and regorafenib for third-line treatment. A number of other TKIs have been tested in phase 2 studies for treatment of GIST in the fourth-line or later clinical setting. Overall, the use of KIT inhibitors has changed the prognosis for patients with metastatic GIST, with median survival increasing from an estimated 1–1.5 years to the current 6–8 years (Barrios et al. 2015). Notably, resistance to KIT inhibitors in KIT-mutant GIST is typically associated with the development of secondary KIT mutations that confer drug resistance (Heinrich et al. 2006, 2008b; Corless et al. 2011; Gramza et al. 2009). Developing new inhibitors to prevent or overcome secondary mutations is a major focus of ongoing GIST research (Blay 2010).
In addition to GIST, some therapeutic progress has been made in treating mast cell neoplasms with KIT kinase inhibitors. Currently, available KIT kinase inhibitors have reduced potency against the KIT D816V mutation associated with mast cell neoplasms (Verstovsek et al. 2008; Vega-Ruiz et al. 2009). However, it is anticipated that development of novel KIT inhibitors that are active against the D816V mutation will be clinically effective for treating mast cell neoplasms. Currently, imatinib is FDA approved for treatment of aggressive mastocytosis lacking the D816V mutation or with an unknown KIT genotype.
Clinical studies using KIT inhibitors to treat unselected cases of malignant melanoma have been disappointing (Wyman et al. 2006). However, KIT kinase inhibitors have shown strong activity against KIT-mutant melanoma (Hodi et al. 2008). Three phase 2 trials for imatinib and two for nilotinib have shown promising responses in KIT-mutant melanoma, specifically in mucosal, acral, and chronically sun-damaged subtypes (Hodi et al. 2013; Guo et al. 2011; Carvajal et al. 2011, 2015; Lee et al. 2015a). The disease control rate for patients with KIT mutations treated with imatinib was 77% (including partial response of 54%). To date, none of the tested KIT inhibitors has been approved by any national health authority agency for treatment of KIT-mutant melanoma.
Anticipated High-Impact Results
-
Final reports from ongoing phase 2 and phase 3 studies of imatinib, sunitinib, or nilotinib for treatment of KIT-mutant melanoma
-
Final analysis of the impact of KIT mutations on the clinical efficacy of adjuvant imatinib after resection of primary GIST
-
Planned phase 1–2 studies of mechanistically novel KIT inhibitors with activity against D816V and other mutations that are resistant to current inhibitors
References
Abrams TJ, Lee LB, Murray LJ, et al. SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Mol Cancer Ther. 2003;2:471–8.
Andersson J, Bumming P, Meis-Kindblom JM, et al. Gastrointestinal stromal tumors with KIT exon 11 deletions are associated with poor prognosis. Gastroenterology. 2006;130:1573–81.
Barrios CH, Blackstein ME, Blay JY, et al. The GOLD ReGISTry: a global, prospective, observational registry collecting longitudinal data on patients with advanced and localised gastrointestinal stromal tumours. Eur J Cancer. 2015;51:2423–33. doi:10.1016/j.ejca.2015.07.010.
Beadling C, Jacobson-Dunlop E, Hodi FS, et al. KIT gene mutations and copy number in melanoma subtypes. Clin Cancer Res. 2008;14:6821–8.
Blay JY. A decade of tyrosine kinase inhibitor therapy: historical and current perspectives on targeted therapy for GIST. Cancer Treat Rev. 2010. doi:10.1016/j.ctrv.2010.11.003.
Broudy VC. Stem cell factor and hematopoiesis. Blood. 1997;90:1345–64.
Buchdunger E, Cioffi CL, Law N, et al. Abl protein-tyrosine kinase inhibitor STI571 inhibits In vitro signal transduction mediated by c-Kit and platelet-derived growth factor receptors. J Pharmacol Exp Ther. 2000;295:139–45.
Carvajal RD, Antonescu CR, Wolchok JD, et al. KIT as a therapeutic target in metastatic melanoma. JAMA. 2011;305:2327–34. doi:10.1001/jama.2011.746.
Carvajal RD, Lawrence DP, Weber JS, et al. Phase II study of nilotinib in melanoma harboring KIT alterations following progression to prior KIT inhibition. Clin Cancer Res. 2015;21:2289–96. doi:10.1158/1078-0432.CCR-14-1630.
Corless CL, Ballman KV, Antonescu C, et al. Relation of tumor pathologic and molecular features to outcome after surgical resection of localized primary gastrointestinal stromal tumor (GIST): results of the intergroup phase III trial ACOSOG Z9001. 28 ed. 2010. p. 15s.
Corless CL, Barnett CM, Heinrich MC. Gastrointestinal stromal tumours: origin and molecular oncology. Nat Rev Cancer. 2011;11:865–78. doi:10.1038/nrc3143.
Craig FE, Foon KA. Flow cytometric immunophenotyping for hematologic neoplasms. Blood. 2008;111:3941–67. doi:10.1182/blood-2007-11-120535.
Debiec-Rychter M, Dumez H, Judson I, et al. Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumours entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer. 2004;40:689–95.
Debiec-Rychter M, Sciot R, Le CA, et al. KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer. 2006;42:1093–103.
DeMatteo RP, Heinrich MC, el-Rifai W, Demetri GD. Clinical management of gastrointestinal stromal tumors: before and after STI-571. Hum Pathol. 2002;33:466–77.
Dexter TM, Moore MAS. In vitro duplication and “cure” of haematopoietic defects in genetically anaemic mice. Nature. 1977;269:412–4.
Gastrointestinal stromal tumours: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25(Suppl 3):iii21–6. doi:10.1093/annonc/mdu255.
Gotlib J, Berube C, Growney JD, et al. Activity of the tyrosine kinase inhibitor PKC412 in a patient with mast cell leukemia with the D816V KIT mutation. Blood. 2005;106:2865–70.
Gramza AW, Corless CL, Heinrich MC. Resistance to tyrosine kinase inhibitors in gastrointestinal stromal tumors. Clin Cancer Res. 2009;15:7510–8. doi:10.1158/1078-0432.CCR-09-0190.
Guo J, Si L, Kong Y, et al. Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. J Clin Oncol. 2011;29:2904–9. doi:10.1200/JCO.2010.33.9275.
Heinrich MC, Griffith DJ, Druker BJ, et al. Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood. 2000;96:925–32.
Heinrich MC, Blanke CD, Druker BJ, Corless CL. Inhibition of KIT tyrosine kinase activity: a novel molecular approach to the treatment of KIT-positive malignancies. J Clin Oncol. 2002;20:1692–703.
Heinrich MC, Corless CL, Demetri GD, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003;21:4342–9. doi:10.1200/JCO.2003.04.190.
Heinrich MC, Corless CL, Blanke CD, et al. Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol. 2006;24:4764–74. doi:10.1200/JCO.2006.06.2265.
Heinrich MC, Owzar K, Corless CL, et al. Correlation of kinase genotype and clinical outcome in the North American Intergroup Phase III Trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 Study by Cancer and Leukemia Group B and Southwest Oncology Group. J Clin Oncol. 2008a;26:5360–7.
Heinrich MC, Maki RG, Corless CL, et al. Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor. J Clin Oncol. 2008b;26:5352–9.
Hodi FS, Friedlander P, Corless CL, et al. Major response to imatinib mesylate in KIT-mutated melanoma. J Clin Oncol. 2008;26:2046–51.
Hodi FS, Corless CL, Giobbie-Hurder A, et al. Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin. J Clin Oncol. 2013;31:3182–90. doi:10.1200/JCO.2012.47.7836.
Hou YY, Grabellus F, Weber F, et al. Impact of KIT and PDGFRA gene mutations on prognosis of patients with gastrointestinal stromal tumors after complete primary tumor resection. J Gastrointest Surg. 2009;13:1583–92. doi:10.1007/s11605-009-0842-6.
Jiang X, Zhou J, Yuen NK, et al. Imatinib targeting of KIT-mutant oncoprotein in melanoma. Clin Cancer Res. 2008;14:7726–32. doi:10.1158/1078-0432.CCR-08-1144.
Joensuu H, Rutkowski P, Nishida T, et al. KIT and PDGFRA mutations and the risk of GI stromal tumor recurrence. J Clin Oncol. 2015;33:634–42. doi:10.1200/JCO.2014.57.4970.
Joensuu H, Eriksson M, Sundby HK, et al. Adjuvant imatinib for high-risk GI stromal tumor: analysis of a randomized trial. J Clin Oncol. 2016;34:244–50. doi:10.1200/JCO.2015.62.9170.
Lee SJ, Kim TM, Kim YJ, et al. Phase II trial of nilotinib in patients with metastatic malignant melanoma harboring KIT gene aberration: a multicenter trial of Korean Cancer Study Group (UN10-06). Oncologist. 2015a;20:1312–9. doi:10.1634/theoncologist.2015-0161.
Lee CK, Goldstein D, Gibbs E, et al. Development and validation of prognostic nomograms for metastatic gastrointestinal stromal tumour treated with imatinib. Eur J Cancer. 2015b;51:852–60. doi:10.1016/j.ejca.2015.02.015.
Lennartsson J, Ronnstrand L. The stem cell factor receptor/c-Kit as a drug target in cancer. Curr Cancer Drug Targets. 2006;6:65–75.
Lennartsson J, Jelacic T, Linnekin D, Shivakrupa R. Normal and oncogenic forms of the receptor tyrosine kinase kit. Stem Cells. 2005;23:16–43.
Ma Y, Carter E, Wang X, et al. Indolinone derivatives inhibit constitutively activated KIT mutants and kill neoplastic mast cells. J Invest Dermatol. 2000;114:392–4.
MetaGIST. Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: a meta-analysis of 1,640 patients. J Clin Oncol. 2010;28:1247–53. doi:10.1200/JCO.2009.24.2099.
Miettinen M, Lasota J. KIT (CD117): a review on expression in normal and neoplastic tissues, and mutations and their clinicopathologic correlation. Appl Immunohistochem Mol Morphol. 2005;13:205–20.
Overton LC, Heinrich MC. Regorafenib for treatment of advanced gastrointestinal stromal tumors. Expert Opin Pharmacother. 2014;15:549–58. doi:10.1517/14656566.2014.877888.
Piccaluga PP, Rondoni M, Paolini S, et al. Imatinib mesylate in the treatment of hematologic malignancies. Expert Opin Biol Ther. 2007;7:1597–611. doi:10.1517/14712598.7.10.1597.
Reichardt P, Demetri GD, Gelderblom H, et al. Correlation of KIT and PDGFRA mutational status with clinical benefit in patients with gastrointestinal stromal tumor treated with sunitinib in a worldwide treatment-use trial. BMC Cancer. 2016;16:22. doi:10.1186/s12885-016-2051-5.
Rubin BP, Heinrich MC. Genotyping and immunohistochemistry of gastrointestinal stromal tumors: an update. Semin Diagn Pathol. 2015. doi:10.1053/j.semdp.2015.02.017.
Schittenhelm MM, Shiraga S, Schroeder A, et al. Dasatinib (BMS-354825), a dual SRC/ABL kinase inhibitor, inhibits the kinase activity of wild-type, juxtamembrane, and activation loop mutant KIT isoforms associated with human malignancies. Cancer Res. 2006;66:473–81.
Shah NP, Lee FY, Luo R, et al. Dasatinib (BMS-354825) inhibits KITD816V, an imatinib-resistant activating mutation that triggers neoplastic growth in most patients with systemic mastocytosis. Blood. 2006;108:286–91.
Turner MS, Goldsmith JD. Best practices in diagnostic immunohistochemistry: spindle cell neoplasms of the gastrointestinal tract. Arch Pathol Lab Med. 2009;133:1370–4. doi:10.1043/1543-2165-133.9.1370.
Tuveson DA, Willis NA, Jacks T, et al. STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: biological and clinical implications. Oncogene. 2001;20:5054–8.
Vega-Ruiz A, Cortes JE, Sever M, et al. Phase II study of imatinib mesylate as therapy for patients with systemic mastocytosis. Leuk Res. 2009;33:1481–4. doi:10.1016/j.leukres.2008.12.020.
Verstovsek S, Tefferi A, Cortes J, et al. Phase II study of dasatinib in Philadelphia chromosome-negative acute and chronic myeloid diseases, including systemic mastocytosis. Clin Cancer Res. 2008;14:3906–15.
von Mehren M, Benjamin RS, Bui MM, et al. Soft tissue sarcoma, version 2.2012: featured updates to the NCCN guidelines. J Natl Compr Canc Netw. 2012;10:951–60.
Wyman K, Atkins MB, Prieto V, et al. Multicenter Phase II trial of high-dose imatinib mesylate in metastatic melanoma: significant toxicity with no clinical efficacy. Cancer. 2006;106:2005–11.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2017 Springer Science+Business Media, New York (outside the USA)
About this entry
Cite this entry
Macleod, A.C., Klug, L.R., Heinrich, M.C. (2017). CKIT. In: Marshall, J. (eds) Cancer Therapeutic Targets. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-0717-2_25
Download citation
DOI: https://doi.org/10.1007/978-1-4419-0717-2_25
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4419-0716-5
Online ISBN: 978-1-4419-0717-2
eBook Packages: Biomedical and Life SciencesReference Module Biomedical and Life Sciences