Genetic alterations associated with acquired temozolomide resistance in SNB-19, a human glioma cell line.
Gliomas are highly lethal neoplasms that cannot be cured by currently available therapies. Temozolomide is a recently introduced alkylating agent that has yielded a significant benefit in the treatment of high-grade gliomas. However, either de novo or acquired chemoresistance occurs frequently and has been attributed to increased levels of O6-methylguanine-DNA methyltransferase or to the loss of mismatch repair capacity. However, very few gliomas overexpress O6-methylguanine-DNA methyltransferase or are mismatch repair-deficient, suggesting that other mechanisms may be involved in the resistance to temozolomide. The purpose of the present study was to generate temozolomide-resistant variants from a human glioma cell line (SNB-19) and to use large-scale genomic and transcriptional analyses to study the molecular basis of acquired temozolomide resistance. Two independently obtained temozolomide-resistant variants exhibited no cross-resistance to other alkylating agents [1,3-bis(2-chloroethyl)-1-nitrosourea and carboplatin] and shared genetic alterations, such as loss of a 2p region and loss of amplification of chromosome 4 and 16q regions. The karyotypic alterations were compatible with clonal selection of preexistent resistant cells in the parental SNB-19 cell line. Microarray analysis showed that 78 out of 17,000 genes were differentially expressed between parental cells and both temozolomide-resistant variants. None are implicated in known resistance mechanisms, such as DNA repair, whereas interestingly, several genes involved in differentiation were down-regulated. The data suggest that the acquisition of resistance to temozolomide in this model resulted from the selection of less differentiated preexistent resistant cells in the parental tumor.
Auger
Nathalie
N
INSERM U612, Research Section, Institut Curie, 26 rue d'Ulm, 75248 Paris Cedex 05, France.
Thillet
Joëlle
J
Wanherdrick
Krystell
K
Idbaih
Ahmed
A
Legrier
Marie-Emmanuelle
ME
Dutrillaux
Bernard
B
Sanson
Marc
M
Poupon
Marie-France
MF
D018906:Antineoplastic Agents, Alkylating / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015870:Gene Expression; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D017404:In Situ Hybridization, Fluorescence / Q000379:methods; D007621:Karyotyping / Q000379:methods; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D000077204:Temozolomide
D018906:Antineoplastic Agents, Alkylating; D012333:RNA, Messenger; D003606:Dacarbazine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000077204:Temozolomide