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Journal of Clinical Oncology, Vol 25, No 9 (March 20), 2007: pp. 1146-1147 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.5331
KIT Mutations and Imatinib Dose Effects in Patients With Gastrointestinal Stromal TumorsDivision of Oncology, Cancer Center, "V. Fazzi" Hospital, Lecce, Italy To the Editor: I read with interest the article by Heinrich et al1 on the molecular mechanisms of imatinib resistance in patients with gastrointestinal stromal tumors (GIST) enrolled onto a randomized phase II trial comparing doses of imatinib of 400 mg/d to 600 mg/d.2 The authors observed that KIT exon 9 mutations were significantly over-represented in the group of patients with primary resistance to imatinib, defined as patients whose tumors progressed during the first 6 months of treatment, whereas GISTs with KIT exon 11 mutations commonly became resistant to imatinib due to acquisition of secondary kinase mutations. The absence of acquired mutations in early progressing KIT exon 9 mutant GISTs coupled with the activation in these tumors of the same signaling pathways (KIT phosphorylation and activation of downstream AKT and MAPK pathways) that are operative in untreated GISTs induced the authors to consider some KIT exon 9 mutant GISTs as primary resistant. I have some concerns about the doses of imatinib and their impact on GIST sensitivity/resistance. Of 10 GIST patients with KIT exon 9 mutations analyzed in the Heinrich et al study, seven patients treated with 600 mg/d of imatinib achieved partial remission (n = 3) and stable disease (n = 4) with a median time to treatment failure (TTF) of 173 days (range, 107 to 766 days), whereas three patients who received 400 mg/d of imatinib achieved stable disease (n = 1) and progressive disease (n = 2) with a median TTF of 74 days (range, 23 to 273 days). Then, patients with GISTs harboring KIT exon 9 mutations benefited from the higher dose of the drug. Debiec-Rychter et al3 have recently assessed the molecular correlates for dose selection for the European Organisation for Research and Treatment of Cancer (EORTC) phase III randomized trial that compares 400 mg/d of imatinib to 800 mg/d in GISTs. In patients whose GISTs expressed KIT exon 9 mutations, high-dose imatinib resulted in a statistically significant superior TTF (P = .0013). Although they were retrospective analyses, both studies showed the efficacy of higher starting doses of imatinib in GISTs with KIT exon 9 mutations. Imatinib competes with ATP for the ATP-binding site of the kinase. Primary KIT exon 9 mutations might lead to a minor degree of binding affinity than that induced by KIT 11 mutations because of a difference in the tridimensional proteic structure of the ATP pocket, but this effect might be subverted by an imatinib dose escalation.4 Moreover, the degree of inhibition might differ during treatment in different patients due to major interpatient variations in imatinib pharmacokinetics, microenvironmental changes, and other unidentified causes.5 Heinrich et al considered some KIT exon 9 mutant GISTs as primary resistant, and speculated that "they have an alternative mechanism of KIT activation that does not require the enzymatic activity of KIT." I feel that their results and recent data suggest that KIT exon 9 mutant GISTs do not represent primary-resistant tumors but actually represent GIST subtypes, depending on the enzymatic activity of KIT with a minor degree of binding affinity of imatinib, because of the conformational structure of the ATP pocket induced by exon 9 mutation that might be in part overcome by higher doses of the drug. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author indicated no potential conflicts of interest. REFERENCES
1. Heinrich MC, Corless CL, Blanke CD, et al: Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol 24:4764-4774, 2006 2. Demetri GD, von Meher M, Blanke CD, et al: Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347:472-480, 2002 3. Debiec-Rychter M, Sciot R, Le Cesne A, et al: KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumors. Eur J Cancer 42:1093-1103, 2006[CrossRef][Medline] 4. Tamborini E, Pricl S, Negri T, et al: Functional analyses and molecular modeling of two c-KIT mutations responsible for imatinib secondary resistance in GIST patients. Oncogene 25:6140-6146, 2006[CrossRef][Medline] 5. De Giorgi U, Verweij J: Imatinib and gastrointestinal stromal tumors: Where do we go from here? Mol Cancer Ther 4:495-501, 2005
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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