Mechanisms of Sunitinib Resistance in Gastrointestinal Stromal Tumors Harboring KITAY502-3ins Mutation: An In vitro Mutagenesis Screen for Drug Resistance

• Published in: Clinical cancer research Vol. 15; no. 22; pp. 6862 - 6870
• Main Authors: Guo, Tianhua, Hajdu, Mihai, Agaram, Narasimhan P, Shinoda, Hiroko, Veach, Darren, Clarkson, Bayard D, Maki, Robert G, Singer, Samuel, Dematteo, Ronald P, Besmer, Peter, Antonescu, Cristina R
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 15-11-2009
• Subjects: Animals; Antineoplastic Agents - pharmacology; Apoptosis; Cell Line; Cell Proliferation; Drug Resistance, Neoplasm; exon 9; Exons; Gastrointestinal Stromal Tumors - drug therapy; Gastrointestinal Stromal Tumors - genetics; Genotype; GIST; Humans; imatinib; Indoles - pharmacology; Mice; Mutagenesis; Mutation; Proto-Oncogene Proteins c-kit - genetics; Pyrroles - pharmacology; sunitinib resistance
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-09-1315

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 KIT AY502-3ins 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 KIT AY502-3ins 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 KIT AY502-3ins 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 KIT AY502-3ins 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):6862–70)