Genomic and molecular profiling predicts response to temozolomide in melanoma.
OBJECTIVE
Despite objective response rates of only approximately 13%, temozolomide remains one of the most effective single chemotherapy agents against metastatic melanoma, second only to dacarbazine, the current standard of care for systemic treatment of melanoma. The goal of this study was to identify molecular and/or genetic markers that correlate with, and could be used to predict, response to temozolomide-based treatment regimens and that reflect the intrinsic properties of a patient's tumor.


METHODS
Using a panel of 26 human melanoma-derived cell lines, we determined in vitro temozolomide sensitivity, O(6)-methylguanine-DNA methyltransferase (MGMT) activity, MGMT protein expression and promoter methylation status, and mismatch repair proficiency, as well as the expression profile of 38,000 genes using an oligonucleotide-based microarray platform.


RESULTS
The results showed a broad spectrum of temozolomide sensitivity across the panel of cell lines, with IC(50) values ranging from 100 micromol/L to 1 mmol/L. There was a significant correlation between measured temozolomide sensitivity and a gene expression signature-derived prediction of temozolomide sensitivity (P < 0.005). Notably, MGMT alone showed a significant correlation with temozolomide sensitivity (MGMT activity, P < 0.0001; MGMT expression, P <or= 0.0001). The promoter methylation status of the MGMT gene, however, was not consistent with MGMT gene expression or temozolomide sensitivity.


CONCLUSIONS
These results show that melanoma resistance to temozolomide is conferred predominantly by MGMT activity and suggest that MGMT expression could potentially be a useful tool for predicting the response of melanoma patients to temozolomide therapy.
Augustine
Christina K
CK
Department of Surgery, and Duke Institute for Genome Sciences and Policy, Duke University Medical Center and Durham VA Medical Center, Durham, North Carolina 27710, USA. Christi.augustine@duke.edu
Yoo
Jin Soo
JS
Potti
Anil
A
Yoshimoto
Yasunori
Y
Zipfel
Patricia A
PA
Friedman
Henry S
HS
Nevins
Joseph R
JR
Ali-Osman
Francis
F
Tyler
Douglas S
DS
D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D019540:Area Under Curve; D045744:Cell Line, Tumor; D019175:DNA Methylation; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics; D006801:Humans; D020128:Inhibitory Concentration 50; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism*; D018895:Microsatellite Repeats; D009362:Neoplasm Metastasis; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000494:pharmacology; D000077204:Temozolomide
D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000077204:Temozolomide