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KIT Activation Is a Ubiquitous Feature of Gastrointestinal Stromal Tumors

Departments of Pathology [B. P. R., C. T., A. D., M. L. L., R. R., M. K. H., C-J. C., S. X., C. D. M. F., J. A. F.] and Surgery [S. S.], Brigham and Women’s Hospital, Boston, Massachusetts 02115, and Departments of Adult Oncology [D. A. T., G. D. D., J. A. F.] and Pediatric Oncology [J. A. F.], Dana Farber Cancer Institute, Boston, Massachusetts 02115

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, and they are generally resistant to chemotherapy and radiation therapy. Most GISTs express the KIT receptor tyrosine kinase protein, and a subset of GISTs contain activating mutations within the KIT juxtamembrane region. We evaluated 48 GISTs, including 10 benign, 10 borderline, and 28 malignant cases, to determine whether KIT expression and activation are general properties of these tumors. Immunohistochemical KIT expression was demonstrated in each case. Somatic KIT mutations were found in 44 tumors (92%), of which 34 (71%) had juxtamembrane region mutations. Other GISTs had KIT mutations in the extracellular region (n = 6) and in two different regions in the tyrosine kinase domain (n = 4). Contrary to previous reports, KIT mutations were not identified preferentially in higher-grade tumors: indeed, they were found in each of 10 histologically benign GISTs. Notably, mutations in all KIT domains were associated with high-level KIT activation/phosphorylation, and KIT activation was also demonstrated in the four GISTs that lacked detectable KIT genomic and cDNA mutations. These studies underscore the role of KIT activation in GIST pathogenesis, and they suggest that activated KIT might represent a universal therapeutic target in GISTs.

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				E. Tamborini, L. Bonadiman, A. Greco, A. Gronchi, C. Riva, R. Bertulli, P. G. Casali, M. A. Pierotti, and S. Pilotti Expression of Ligand-Activated KIT and Platelet-Derived Growth Factor Receptor {beta} Tyrosine Kinase Receptors in Synovial Sarcoma Clin. Cancer Res., February 1, 2004; 10(3): 938 - 943. [Abstract] [Full Text] [PDF]

				I. Gonzalez, E. J. Andreu, A. Panizo, S. Inoges, A. Fontalba, J. L. Fernandez-Luna, M. Gaboli, L. Sierrasesumaga, S. Martin-Algarra, J. Pardo, et al. Imatinib Inhibits Proliferation of Ewing Tumor Cells Mediated by the Stem Cell Factor/KIT Receptor Pathway, and Sensitizes Cells to Vincristine and Doxorubicin-Induced Apoptosis Clin. Cancer Res., January 15, 2004; 10(2): 751 - 761. [Abstract] [Full Text] [PDF]

				K. Kemmer, C. L. Corless, J. A. Fletcher, L. McGreevey, A. Haley, D. Griffith, O. W. Cummings, C. Wait, A. Town, and M. C. Heinrich KIT Mutations Are Common in Testicular Seminomas Am. J. Pathol., January 1, 2004; 164(1): 305 - 313. [Abstract] [Full Text] [PDF]

				M. C. Heinrich, C. L. Corless, G. D. Demetri, C. D. Blanke, M. von Mehren, H. Joensuu, L. S. McGreevey, C.-J. Chen, A. D. Van den Abbeele, B. J. Druker, et al. Kinase Mutations and Imatinib Response in Patients With Metastatic Gastrointestinal Stromal Tumor J. Clin. Oncol., December 1, 2003; 21(23): 4342 - 4349. [Abstract] [Full Text] [PDF]

				M. C. Heinrich Is KIT an Important Therapeutic Target in Small Cell Lung Cancer?: Commentary re: B. E. Johnson et al., Phase II Study of Imatinib in Patients with Small Cell Lung Cancer. Clin. Cancer Res., 9: 5880-5887, 2003. Clin. Cancer Res., December 1, 2003; 9(16): 5825 - 5828. [Full Text] [PDF]

				B. J. Druker Imatinib As a Paradigm of Targeted Therapies J. Clin. Oncol., December 1, 2003; 21(90230): 239s - 245. [Full Text] [PDF]

				T. O. Nielsen, F. D. Hsu, J. X. O'Connell, C. B. Gilks, P. H.B. Sorensen, S. Linn, R. B. West, C. L. Liu, D. Botstein, P. O. Brown, et al. Tissue Microarray Validation of Epidermal Growth Factor Receptor and SALL2 in Synovial Sarcoma with Comparison to Tumors of Similar Histology Am. J. Pathol., October 1, 2003; 163(4): 1449 - 1456. [Abstract] [Full Text] [PDF]

				A. Frolov, S. Chahwan, M. Ochs, J. P. Arnoletti, Z.-Z. Pan, O. Favorova, J. Fletcher, M. von Mehren, B. Eisenberg, and A. K. Godwin Response Markers and the Molecular Mechanisms of Action of Gleevec in Gastrointestinal Stromal Tumors Mol. Cancer Ther., August 1, 2003; 2(8): 699 - 709. [Abstract] [Full Text] [PDF]

				R. Komdeur, H. J. Hoekstra, W. M. Molenaar, E. van den Berg, N. Zwart, E. Pras, I. Plaza-Menacho, R. M. W. Hofstra, and W. T. A. van der Graaf Clinicopathologic Assessment of Postradiation Sarcomas: KIT as a Potential Treatment Target Clin. Cancer Res., August 1, 2003; 9(8): 2926 - 2932. [Abstract] [Full Text] [PDF]

				C. R. Antonescu, G. Sommer, L. Sarran, S. J. Tschernyavsky, E. Riedel, J. M. Woodruff, M. Robson, R. Maki, M. F. Brennan, M. Ladanyi, et al. Association of KIT Exon 9 Mutations with Nongastric Primary Site and Aggressive Behavior: KIT Mutation Analysis and Clinical Correlates of 120 Gastrointestinal Stromal Tumors Clin. Cancer Res., August 1, 2003; 9(9): 3329 - 3337. [Abstract] [Full Text] [PDF]

				C. A. London, A. L. Hannah, R. Zadovoskaya, M. B. Chien, C. Kollias-Baker, M. Rosenberg, S. Downing, G. Post, J. Boucher, N. Shenoy, et al. Phase I Dose-Escalating Study of SU11654, a Small Molecule Receptor Tyrosine Kinase Inhibitor, in Dogs with Spontaneous Malignancies Clin. Cancer Res., July 1, 2003; 9(7): 2755 - 2768. [Abstract] [Full Text] [PDF]

				G. Sommer, V. Agosti, I. Ehlers, F. Rossi, S. Corbacioglu, J. Farkas, M. Moore, K. Manova, C. R. Antonescu, and P. Besmer Gastrointestinal stromal tumors in a mouse model by targeted mutation of the Kit receptor tyrosine kinase PNAS, May 27, 2003; 100(11): 6706 - 6711. [Abstract] [Full Text] [PDF]

				K. Scotlandi, M. C. Manara, R. Strammiello, L. Landuzzi, S. Benini, S. Perdichizzi, M. Serra, A. Astolfi, G. Nicoletti, P.-L. Lollini, et al. c-kit Receptor Expression in Ewing's Sarcoma: Lack of Prognostic Value but Therapeutic Targeting Opportunities in Appropriate Conditions J. Clin. Oncol., May 15, 2003; 21(10): 1952 - 1960. [Abstract] [Full Text] [PDF]

				G. Fiorentini, S. Rossi, G. Lanzanova, P. Bernardeschi, P. Dentico, and U. De Giorgi Potential use of imatinib mesylate in ocular melanoma and liposarcoma expressing immunohistochemical c-KIT (CD117) Ann. Onc., May 1, 2003; 14(5): 805 - 805. [Full Text] [PDF]

				Y. R. Choi, H. Kim, H. J. Kang, N.-G. Kim, J. J. Kim, K.-S. Park, Y.-K. Paik, H. O. Kim, and H. Kim Overexpression of High Mobility Group Box 1 in Gastrointestinal Stromal Tumors with KIT Mutation Cancer Res., May 1, 2003; 63(9): 2188 - 2193. [Abstract] [Full Text] [PDF]

				R. Schneider-Stock, C. Boltze, J. Lasota, M. Miettinen, B. Peters, M. Pross, A. Roessner, and T. Gunther High Prognostic Value of p16INK4 Alterations in Gastrointestinal Stromal Tumors J. Clin. Oncol., May 1, 2003; 21(9): 1688 - 1697. [Abstract] [Full Text] [PDF]

				M. C. Heinrich, C. L. Corless, A. Duensing, L. McGreevey, C.-J. Chen, N. Joseph, S. Singer, D. J. Griffith, A. Haley, A. Town, et al. PDGFRA Activating Mutations in Gastrointestinal Stromal Tumors Science, January 31, 2003; 299(5607): 708 - 710. [Abstract] [Full Text] [PDF]

				D. P. Ryan, T. Puchalski, J. G. Supko, D. Harmon, R. Maki, R. Garcia-Carbonero, C. Kuhlman, J. Winkelman, P. Merriam, T. Quigley, et al. A Phase II and Pharmacokinetic Study of Ecteinascidin 743 in Patients with Gastrointestinal Stromal Tumors Oncologist, December 1, 2002; 7(6): 531 - 538. [Abstract] [Full Text] [PDF]

				S. Singer, B. P. Rubin, M. L. Lux, C.-J. Chen, G. D. Demetri, C. D.M. Fletcher, and J. A. Fletcher Prognostic Value of KIT Mutation Type, Mitotic Activity, and Histologic Subtype in Gastrointestinal Stromal Tumors J. Clin. Oncol., September 15, 2002; 20(18): 3898 - 3905. [Abstract] [Full Text] [PDF]

				S. Attoub, C. Rivat, S. Rodrigues, S. Van Bocxlaer, M. Bedin, E. Bruyneel, C. Louvet, M. Kornprobst, T. Andre, M. Mareel, et al. The c-kit Tyrosine Kinase Inhibitor STI571 for Colorectal Cancer Therapy Cancer Res., September 1, 2002; 62(17): 4879 - 4883. [Abstract] [Full Text] [PDF]

				G. D. Demetri, M. von Mehren, C. D. Blanke, A. D. Van den Abbeele, B. Eisenberg, P. J. Roberts, M. C. Heinrich, D. A. Tuveson, S. Singer, M. Janicek, et al. Efficacy and Safety of Imatinib Mesylate in Advanced Gastrointestinal Stromal Tumors N. Engl. J. Med., August 15, 2002; 347(7): 472 - 480. [Abstract] [Full Text] [PDF]

				J. A. Fletcher, C. D.M. Fletcher, B. P. Rubin, L. K. Ashman, C. L. Corless, M. C. Heinrich, J. Andersson, H. Sjogren, J. Meis-Kindblom, G. Stenman, et al. KIT Gene Mutations in Gastrointestinal Stromal Tumors : More Complex than Previously Recognized? Am. J. Pathol., August 1, 2002; 161(2): 737 - 739. [Full Text] [PDF]

				J. Lasota, J. Kopczynski, M. Majidi, M. Miettinen, and M. Sarlomo-Rikala Apparent KIT Ser715 Deletion in GIST mRNA Is Not Detectable in Genomic DNA and Represents a Previously Known Splice Variant of KIT Transcript Am. J. Pathol., August 1, 2002; 161(2): 739 - 741. [Full Text] [PDF]

				A. I. Spira and D. S. Ettinger The Use of Chemotherapy in Soft-Tissue Sarcomas Oncologist, August 1, 2002; 7(4): 348 - 359. [Abstract] [Full Text] [PDF]

				A. T. Liao, M. B. Chien, N. Shenoy, D. B. Mendel, G. McMahon, J. M. Cherrington, and C. A. London Inhibition of constitutively active forms of mutant kit by multitargeted indolinone tyrosine kinase inhibitors Blood, June 28, 2002; 100(2): 585 - 593. [Abstract] [Full Text] [PDF]

				C. L. Corless, L. McGreevey, A. Haley, A. Town, and M. C. Heinrich KIT Mutations Are Common in Incidental Gastrointestinal Stromal Tumors One Centimeter or Less in Size Am. J. Pathol., May 1, 2002; 160(5): 1567 - 1572. [Abstract] [Full Text] [PDF]