Mechanisms of sunitinib resistance in gastrointestinal stromal tumors harboring KITAY502-3ins mutation: an in vitro mutagenesis screen for drug resistance.
OBJECTIVE
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.


METHODS
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.
Departments of Pathology, Medicine, and Surgery, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Institute, New York, NY 10021, USA.
Tianhua
T
Guo
Mihai
M
Hajdu
Narasimhan P
NP
Agaram
Hiroko
H
Shinoda
Darren
D
Veach
Bayard D
BD
Clarkson
Robert G
RG
Maki
Samuel
S
Singer
Ronald P
RP
Dematteo
Peter
P
Besmer
Cristina R
CR
Antonescu
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D002460:Cell Line; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D005091:Exons; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D016296:Mutagenesis; D009154:Mutation; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D011758:Pyrroles / Q000494:pharmacology*; D000077210:Sunitinib
D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D019009:Proto-Oncogene Proteins c-kit; D000077210:Sunitinib