Originally published as JCO Early Release 10.1200/JCO.2006.06.2265 on September 5 2006

This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Heinrich, M. C. Articles by Fletcher, J. A. Search for Related Content PubMed PubMed Citation Articles by Heinrich, M. C. Articles by Fletcher, J. A. Related Articles Related Correspondence Social Bookmarking                            What's this?

Molecular Correlates of Imatinib Resistance in Gastrointestinal Stromal Tumors

Michael C. Heinrich, Christopher L. Corless, Charles D. Blanke, George D. Demetri, Heikki Joensuu, Peter J. Roberts, Burton L. Eisenberg, Margaret von Mehren, Christopher D.M. Fletcher, Katrin Sandau, Karen McDougall, Wen-bin Ou, Chang-Jie Chen, Jonathan A. Fletcher

From the Division of Hematology/Oncology, Department of Pathology, Oregon Health & Science University Cancer Institute, Oregon Health & Science University; Portland Veterans Affairs Medical Center, Portland, OR; Dana-Farber Cancer Institute; Harvard Cancer Center; Department of Pathology, Brigham & Women's Hospital, Boston, MA; Division of Oncologic Surgery, Hitchcock-Dartmouth Medical Center, Lebanon, NH; Division of Medical Oncology, Fox-Chase Cancer Center, Philadelphia, PA; Novartis Pharmaceuticals Corporation, Hanover, NJ; University of Helsinki, Helsinki; and the Department of Surgery, University of Turku, Turku, Finland

Address reprint requests to Michael C. Heinrich, MD, R&D-19 3710 U.S. Veterans Hospital Rd, Portland, OR 97239; e-mail: Heinrich{at}ohsu.edu

PURPOSE: Gastrointestinal stromal tumors (GISTs) commonly harbor oncogenic mutations of the KIT or platelet-derived growth factor alpha (PDGFRA) kinases, which are targets for imatinib. In clinical studies, 75% to 90% of patients with advanced GISTs experience clinical benefit from imatinib. However, imatinib resistance is an increasing clinical problem.

PATIENTS AND METHODS: One hundred forty-seven patients with advanced, unresectable GISTs were enrolled onto a randomized, phase II clinical study of imatinib. Specimens from pretreatment and/or imatinib-resistant tumors were analyzed to identify molecular correlates of imatinib resistance. Secondary kinase mutations of KIT or PDGFRA that were identified in imatinib-resistant GISTs were biochemically profiled for imatinib sensitivity.

RESULTS: Molecular studies were performed using specimens from 10 patients with primary and 33 patients with secondary resistance. Imatinib-resistant tumors had levels of activated KIT that were similar to or greater than those typically found in untreated GISTs. Secondary kinase mutations were rare in GISTs with primary resistance but frequently found in GISTs with secondary resistance (10% v 67%; P = .002). Evidence for clonal evolution and/or polyclonal secondary kinase mutations was seen in three (18.8%) of 16 patients. Secondary kinase mutations were nonrandomly distributed and were associated with decreased imatinib sensitivity compared with typical KIT exon 11 mutations. Using RNAi technology, we demonstrated that imatinib-resistant GIST cells remain dependent on KIT kinase activity for activation of critical downstream signaling pathways.

CONCLUSION: Different molecular mechanisms are responsible for primary and secondary imatinib resistance in GISTs. These findings have implications for future approaches to the growing problem of imatinib resistance in patients with advanced GISTs.

published online ahead of print at www.jco.org on September 5, 2006.

Supported in part by Novartis Pharmaceuticals, VA Merit Review Grant (M.C.H.), GIST Cancer Research Fund (M.C.H.), B.P., Lester and Regina John Foundation (M.C.H.).

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

Related Correspondence

• KIT Mutations and Imatinib Dose Effects in Patients With Gastrointestinal Stromal Tumors
  Ugo De Giorgi
  JCO 2007 25: 1146-1147 [Full Text]

This article has been cited by other articles:

				G. D. Demetri, Y. Wang, E. Wehrle, A. Racine, Z. Nikolova, C. D. Blanke, H. Joensuu, and M. von Mehren Imatinib Plasma Levels Are Correlated With Clinical Benefit in Patients With Unresectable/Metastatic Gastrointestinal Stromal Tumors J. Clin. Oncol., July 1, 2009; 27(19): 3141 - 3147. [Abstract] [Full Text] [PDF]

				G. Floris, M. Debiec-Rychter, R. Sciot, C. Stefan, S. Fieuws, K. Machiels, P. Atadja, A. Wozniak, G. Faa, and P. Schoffski High Efficacy of Panobinostat Towards Human Gastrointestinal Stromal Tumors in a Xenograft Mouse Model Clin. Cancer Res., June 15, 2009; 15(12): 4066 - 4076. [Abstract] [Full Text] [PDF]

				S. Romeo, M. Debiec-Rychter, M. Van Glabbeke, H. Van Paassen, P. Comite, R. Van Eijk, J. Oosting, J. Verweij, P. Terrier, U. Schneider, et al. Cell Cycle/Apoptosis Molecule Expression Correlates with Imatinib Response in Patients with Advanced Gastrointestinal Stromal Tumors Clin. Cancer Res., June 15, 2009; 15(12): 4191 - 4198. [Abstract] [Full Text] [PDF]

				J.-Y. Blay New paradigms in gastrointestinal stromal tumour management Ann. Onc., May 1, 2009; 20(suppl_1): i18 - i24. [Abstract] [Full Text] [PDF]

				N. von Bubnoff, R. A. Engh, E. Aberg, J. Sanger, C. Peschel, and J. Duyster FMS-Like Tyrosine Kinase 3-Internal Tandem Duplication Tyrosine Kinase Inhibitors Display a Nonoverlapping Profile of Resistance Mutations In vitro Cancer Res., April 1, 2009; 69(7): 3032 - 3041. [Abstract] [Full Text] [PDF]

				J. S. Lagas, R. A.B. van Waterschoot, V. A.C.J. van Tilburg, M. J. Hillebrand, N. Lankheet, H. Rosing, J. H. Beijnen, and A. H. Schinkel Brain Accumulation of Dasatinib Is Restricted by P-Glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2) and Can Be Enhanced by Elacridar Treatment Clin. Cancer Res., April 1, 2009; 15(7): 2344 - 2351. [Abstract] [Full Text] [PDF]

				T. Negri, G. M. Pavan, E. Virdis, A. Greco, M. Fermeglia, M. Sandri, S. Pricl, M. A. Pierotti, S. Pilotti, and E. Tamborini T670X KIT Mutations in Gastrointestinal Stromal Tumors: Making Sense of Missense J Natl Cancer Inst, February 4, 2009; 101(3): 194 - 204. [Abstract] [Full Text] [PDF]

				K. S. Gajiwala, J. C. Wu, J. Christensen, G. D. Deshmukh, W. Diehl, J. P. DiNitto, J. M. English, M. J. Greig, Y.-A. He, S. L. Jacques, et al. KIT kinase mutants show unique mechanisms of drug resistance to imatinib and sunitinib in gastrointestinal stromal tumor patients PNAS, February 3, 2009; 106(5): 1542 - 1547. [Abstract] [Full Text] [PDF]

				I. Park, M.-H. Ryu, S. J. Sym, S. S. Lee, G. Jang, T. W. Kim, H. M. Chang, J.-L. Lee, H. Lee, and Y.-K. Kang Dose Escalation of Imatinib After Failure of Standard Dose in Korean Patients with Metastatic or Unresectable Gastrointestinal Stromal Tumor Jpn. J. Clin. Oncol., February 1, 2009; 39(2): 105 - 110. [Abstract] [Full Text] [PDF]

				H. Huynh, J. W.J. Lee, P. K.H. Chow, V. C. Ngo, G. B. Lew, I. W.L. Lam, H. S. Ong, A. Chung, and K. C. Soo Sorafenib induces growth suppression in mouse models of gastrointestinal stromal tumor Mol. Cancer Ther., January 1, 2009; 8(1): 152 - 159. [Abstract] [Full Text] [PDF]

				M. C. Heinrich, S. George, S. Bauer, and J. A. Fletcher Optimizing the Treatment of Gastrointestinal Stromal Tumors: The Roles of Tumor Genotyping, Imatinib Blood-level Testing, and New Therapeutic Strategies ASCO Educational Book, January 1, 2009; 2009(1): 694 - 699. [Abstract] [Full Text] [PDF]

				C.-F. Li, W.-W. Huang, J.-M. Wu, S.-C. Yu, T.-H. Hu, Y.-H. Uen, Y.-F. Tian, C.-N. Lin, D. Lu, F.-M. Fang, et al. Heat Shock Protein 90 Overexpression Independently Predicts Inferior Disease-Free Survival with Differential Expression of the {alpha} and {beta} Isoforms in Gastrointestinal Stromal Tumors Clin. Cancer Res., December 1, 2008; 14(23): 7822 - 7831. [Abstract] [Full Text] [PDF]

				M. C. Heinrich, R. G. Maki, C. L. Corless, C. R. Antonescu, A. Harlow, D. Griffith, A. Town, A. Mckinley, W.-B. Ou, J. A. Fletcher, 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., November 20, 2008; 26(33): 5352 - 5359. [Abstract] [Full Text] [PDF]

				I. R. Judson Prognosis, Imatinib Dose, and Benefit of Sunitinib in GIST: Knowing the Genotype J. Clin. Oncol., November 20, 2008; 26(33): 5322 - 5325. [Full Text] [PDF]

				S. Yano, W. Wang, Q. Li, K. Matsumoto, H. Sakurama, T. Nakamura, H. Ogino, S. Kakiuchi, M. Hanibuchi, Y. Nishioka, et al. Hepatocyte Growth Factor Induces Gefitinib Resistance of Lung Adenocarcinoma with Epidermal Growth Factor Receptor-Activating Mutations Cancer Res., November 15, 2008; 68(22): 9479 - 9487. [Abstract] [Full Text] [PDF]

				C. Beadling, E. Jacobson-Dunlop, F. S. Hodi, C. Le, A. Warrick, J. Patterson, A. Town, A. Harlow, F. Cruz III, S. Azar, et al. KIT Gene Mutations and Copy Number in Melanoma Subtypes Clin. Cancer Res., November 1, 2008; 14(21): 6821 - 6828. [Abstract] [Full Text] [PDF]

				C. H. Chau, O. Rixe, H. McLeod, and W. D. Figg Validation of Analytic Methods for Biomarkers Used in Drug Development Clin. Cancer Res., October 1, 2008; 14(19): 5967 - 5976. [Abstract] [Full Text] [PDF]

				D. Gasparotto, S. Rossi, I. Bearzi, C. Doglioni, A. Marzotto, J. L. Hornick, A. Grizzo, C. Sartor, A. Mandolesi, R. Sciot, et al. Multiple Primary Sporadic Gastrointestinal Stromal Tumors in the Adult: An Underestimated Entity Clin. Cancer Res., September 15, 2008; 14(18): 5715 - 5721. [Abstract] [Full Text] [PDF]

				C. Montagut, S. V. Sharma, T. Shioda, U. McDermott, M. Ulman, L. E. Ulkus, D. Dias-Santagata, H. Stubbs, D. Y. Lee, A. Singh, et al. Elevated CRAF as a Potential Mechanism of Acquired Resistance to BRAF Inhibition in Melanoma Cancer Res., June 15, 2008; 68(12): 4853 - 4861. [Abstract] [Full Text] [PDF]

				M. C. Heinrich, H. Joensuu, G. D. Demetri, C. L. Corless, J. Apperley, J. A. Fletcher, D. Soulieres, S. Dirnhofer, A. Harlow, A. Town, et al. Phase II, Open-Label Study Evaluating the Activity of Imatinib in Treating Life-Threatening Malignancies Known to Be Associated with Imatinib-Sensitive Tyrosine Kinases Clin. Cancer Res., May 1, 2008; 14(9): 2717 - 2725. [Abstract] [Full Text] [PDF]

				T. Trowe, S. Boukouvala, K. Calkins, R. E. Cutler Jr., R. Fong, R. Funke, S. B. Gendreau, Y. D. Kim, N. Miller, J. R. Woolfrey, et al. EXEL-7647 Inhibits Mutant Forms of ErbB2 Associated with Lapatinib Resistance and Neoplastic Transformation Clin. Cancer Res., April 15, 2008; 14(8): 2465 - 2475. [Abstract] [Full Text] [PDF]

				C. Braconi, R. Bracci, I. Bearzi, F. Bianchi, A. Costagliola, R. Catalani, A. Mandolesi, R. Ranaldi, E. Galizia, S. Cascinu, et al. KIT and PDGFR{alpha} mutations in 104 patients with gastrointestinal stromal tumors (GISTs): a population-based study Ann. Onc., April 1, 2008; 19(4): 706 - 710. [Abstract] [Full Text] [PDF]

				Y. Suehara, T. Kondo, K. Seki, T. Shibata, K. Fujii, M. Gotoh, T. Hasegawa, Y. Shimada, M. Sasako, T. Shimoda, et al. Pfetin as a Prognostic Biomarker of Gastrointestinal Stromal Tumors Revealed by Proteomics Clin. Cancer Res., March 15, 2008; 14(6): 1707 - 1717. [Abstract] [Full Text] [PDF]

				H. Joensuu, F. De Braud, P. Coco, T. De Pas, C. Putzu, C. Spreafico, P. Bono, S. Bosselli, T. Jalava, D. Laurent, et al. Phase II, open-label study of PTK787/ZK222584 for the treatment of metastatic gastrointestinal stromal tumors resistant to imatinib mesylate Ann. Onc., January 1, 2008; 19(1): 173 - 177. [Abstract] [Full Text] [PDF]

				C. E. de Kogel and J. H. M. Schellens Imatinib Oncologist, December 1, 2007; 12(12): 1390 - 1394. [Full Text] [PDF]

				K. M. Skubitz and D. R. D'Adamo Sarcoma Mayo Clin. Proc., November 1, 2007; 82(11): 1409 - 1432. [Abstract] [Full Text] [PDF]

				K. A. Janeway, B. Liegl, A. Harlow, C. Le, A. Perez-Atayde, H. Kozakewich, C. L. Corless, M. C. Heinrich, and J. A. Fletcher Pediatric KIT Wild-Type and Platelet-Derived Growth Factor Receptor {alpha} Wild-Type Gastrointestinal Stromal Tumors Share KIT Activation but not Mechanisms of Genetic Progression with Adult Gastrointestinal Stromal Tumors Cancer Res., October 1, 2007; 67(19): 9084 - 9088. [Abstract] [Full Text] [PDF]

				A. K. Todd, S. M. Haider, G. N. Parkinson, and S. Neidle Sequence occurrence and structural uniqueness of a G-quadruplex in the human c-kit promoter Nucleic Acids Res., September 27, 2007; 35(17): 5799 - 5808. [Abstract] [Full Text] [PDF]

				T. Guo, N. P. Agaram, G. C. Wong, G. Hom, D. D'Adamo, R. G. Maki, G. K. Schwartz, D. Veach, B. D. Clarkson, S. Singer, et al. Sorafenib Inhibits the Imatinib-Resistant KITT670I Gatekeeper Mutation in Gastrointestinal Stromal Tumor Clin. Cancer Res., August 15, 2007; 13(16): 4874 - 4881. [Abstract] [Full Text] [PDF]

				T. Guida, S. Anaganti, L. Provitera, R. Gedrich, E. Sullivan, S. M. Wilhelm, M. Santoro, and F. Carlomagno Sorafenib Inhibits Imatinib-Resistant KIT and Platelet-Derived Growth Factor Receptor {beta} Gatekeeper Mutants Clin. Cancer Res., June 1, 2007; 13(11): 3363 - 3369. [Abstract] [Full Text] [PDF]

				S. Sleijfer, E. Wiemer, C. Seynaeve, and J. Verweij Improved Insight into Resistance Mechanisms to Imatinib in Gastrointestinal Stromal Tumors: A Basis for Novel Approaches and Individualization of Treatment Oncologist, June 1, 2007; 12(6): 719 - 726. [Abstract] [Full Text] [PDF]

				J. A. Engelman, K. Zejnullahu, T. Mitsudomi, Y. Song, C. Hyland, J. O. Park, N. Lindeman, C.-M. Gale, X. Zhao, J. Christensen, et al. MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling Science, May 18, 2007; 316(5827): 1039 - 1043. [Abstract] [Full Text] [PDF]

				F.=C> Miselli, P. Casieri, T. Negri, M. Orsenigo, M. S. Lagonigro, A. Gronchi, M. Fiore, P. G. Casali, R. Bertulli, A. Carbone, et al. c-Kit/PDGFRA Gene Status Alterations Possibly Related to Primary Imatinib Resistance in Gastrointestinal Stromal Tumors Clin. Cancer Res., April 15, 2007; 13(8): 2369 - 2377. [Abstract] [Full Text] [PDF]

				U. De Giorgi KIT Mutations and Imatinib Dose Effects in Patients With Gastrointestinal Stromal Tumors J. Clin. Oncol., March 20, 2007; 25(9): 1146 - 1147. [Full Text] [PDF]

				M. C. Heinrich and C. L. Corless In Reply J. Clin. Oncol., March 20, 2007; 25(9): 1147 - 1148. [Full Text] [PDF]