Mechanisms of Sunitinib Resistance in Gastrointestinal Stromal Tumors Harboring KITAY502-3ins Mutation: An In vitro Mutagenesis Screen for Drug Resistance
Autor: | Mihai Hajdu, Hiroko Shinoda, Robert G. Maki, Tianhua Guo, Peter Besmer, Cristina R. Antonescu, Bayard D. Clarkson, Narasimhan P. Agaram, Darren R. Veach, Ronald P. DeMatteo, Samuel Singer |
---|---|
Rok vydání: | 2009 |
Předmět: |
Cancer Research
Indoles Genotype Gastrointestinal Stromal Tumors medicine.drug_class Antineoplastic Agents Apoptosis Biology medicine.disease_cause Article Tyrosine-kinase inhibitor Cell Line Mice Sunitinib medicine Animals Humans Pyrroles Cell Proliferation Mutation Imatinib Exons Sunitinib malate Dasatinib Proto-Oncogene Proteins c-kit Oncology Nilotinib Drug Resistance Neoplasm Mutagenesis Cancer research Tyrosine kinase medicine.drug |
Zdroj: | Clinical Cancer Research. 15:6862-6870 |
ISSN: | 1557-3265 1078-0432 |
Popis: | Purpose: Although tyrosine kinase inhibitors have improved survival in advanced gastrointestinal stromal tumor (GIST), complete response is rare and most patients eventually fail the first-line treatment with imatinib. Sunitinib malate is the only approved second-line therapy for patients with imatinib-resistant or imatinib-intolerant GIST. The clinical benefit of sunitinib is genotype-dependent in regards to both primary and secondary mutations, with GIST patients harboring the KITAY502-3ins exon 9 mutation being the most sensitive. Experimental Design: As sunitinib resistance is now emerging, our goal was to investigate mechanisms of progression and to test the efficacy of novel tyrosine kinase inhibitor on these resistant mutants in vitro. N-ethyl-N-nitrosourea mutagenesis of Ba/F3 cells expressing the KITAY502-3ins mutant was used to investigate novel patterns of resistant mutations evolving in the presence of sunitinib. Results: Tumors from patients who developed sunitinib resistance after at least 1 year of radiographic response were analyzed, showing similar findings of a primary KITAY502-3ins mutation and a secondary mutation in the KIT activation loop. Ba/F3 cells expressing these sunitinib-resistant double mutants showed sensitivity to both dasatinib and nilotinib. Conclusions: Sunitinib resistance in GIST shares similar pathogenetic mechanisms identified in imatinib failure, with acquisition of secondary mutations in the activation domain after an extended initial response to the drug. Moreover, in vitro mutagenesis with or without N-ethyl-N-nitrosourea of Ba/F3 cells expressing KITAY502-3ins showed acquisition of secondary mutations restricted to the second kinase domain of KIT. In contrast, in vitro resistance to imatinib produces a broader spectrum of secondary mutations including mutations in both KIT kinase domains. (Clin Cancer Res 2009;15(22):686270) |
Databáze: | OpenAIRE |
Externí odkaz: |