Genomic and molecular profiling predicts response to temozolomide in melanoma

Christina K. Augustine, Jin Soo Yoo, Anil Potti, Yasunori Yoshimoto, Patricia A. Zipfel, Henry S. Friedman, Joseph R. Nevins, Francis Ali-Osman, Douglas Tyler

Research output: Contribution to journalArticle

76 Citations (Scopus)

Abstract

Purpose: Despite objective response rates of only ∼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. Experimental Design: Using a panel of 26 human melanoma-derived cell lines, we determined in vitro temozolomide sensitivity, O 6-methylguanine-DNA methyltransferase (MGMT) activity, MGMT 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 μmol/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 ≤ 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.

Original languageEnglish (US)
Pages (from-to)502-510
Number of pages9
JournalClinical Cancer Research
Volume15
Issue number2
DOIs
StatePublished - Jan 15 2009
Externally publishedYes

Fingerprint

temozolomide
Melanoma
Methyltransferases
DNA
Methylation
O(6)-Methylguanine-DNA Methyltransferase
Cell Line
Dacarbazine
DNA Mismatch Repair

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Augustine, C. K., Yoo, J. S., Potti, A., Yoshimoto, Y., Zipfel, P. A., Friedman, H. S., ... Tyler, D. (2009). Genomic and molecular profiling predicts response to temozolomide in melanoma. Clinical Cancer Research, 15(2), 502-510. https://doi.org/10.1158/1078-0432.CCR-08-1916

Genomic and molecular profiling predicts response to temozolomide in melanoma. / Augustine, Christina K.; Yoo, Jin Soo; Potti, Anil; Yoshimoto, Yasunori; Zipfel, Patricia A.; Friedman, Henry S.; Nevins, Joseph R.; Ali-Osman, Francis; Tyler, Douglas.

In: Clinical Cancer Research, Vol. 15, No. 2, 15.01.2009, p. 502-510.

Research output: Contribution to journalArticle

Augustine, CK, Yoo, JS, Potti, A, Yoshimoto, Y, Zipfel, PA, Friedman, HS, Nevins, JR, Ali-Osman, F & Tyler, D 2009, 'Genomic and molecular profiling predicts response to temozolomide in melanoma', Clinical Cancer Research, vol. 15, no. 2, pp. 502-510. https://doi.org/10.1158/1078-0432.CCR-08-1916
Augustine CK, Yoo JS, Potti A, Yoshimoto Y, Zipfel PA, Friedman HS et al. Genomic and molecular profiling predicts response to temozolomide in melanoma. Clinical Cancer Research. 2009 Jan 15;15(2):502-510. https://doi.org/10.1158/1078-0432.CCR-08-1916
Augustine, Christina K. ; Yoo, Jin Soo ; Potti, Anil ; Yoshimoto, Yasunori ; Zipfel, Patricia A. ; Friedman, Henry S. ; Nevins, Joseph R. ; Ali-Osman, Francis ; Tyler, Douglas. / Genomic and molecular profiling predicts response to temozolomide in melanoma. In: Clinical Cancer Research. 2009 ; Vol. 15, No. 2. pp. 502-510.
@article{b51d2e739a1442bbb860f313b3fd88c4,
title = "Genomic and molecular profiling predicts response to temozolomide in melanoma",
abstract = "Purpose: Despite objective response rates of only ∼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. Experimental Design: Using a panel of 26 human melanoma-derived cell lines, we determined in vitro temozolomide sensitivity, O 6-methylguanine-DNA methyltransferase (MGMT) activity, MGMT 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 μmol/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 ≤ 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.",
author = "Augustine, {Christina K.} and Yoo, {Jin Soo} and Anil Potti and Yasunori Yoshimoto and Zipfel, {Patricia A.} and Friedman, {Henry S.} and Nevins, {Joseph R.} and Francis Ali-Osman and Douglas Tyler",
year = "2009",
month = "1",
day = "15",
doi = "10.1158/1078-0432.CCR-08-1916",
language = "English (US)",
volume = "15",
pages = "502--510",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "2",

}

TY - JOUR

T1 - Genomic and molecular profiling predicts response to temozolomide in melanoma

AU - Augustine, Christina K.

AU - Yoo, Jin Soo

AU - Potti, Anil

AU - Yoshimoto, Yasunori

AU - Zipfel, Patricia A.

AU - Friedman, Henry S.

AU - Nevins, Joseph R.

AU - Ali-Osman, Francis

AU - Tyler, Douglas

PY - 2009/1/15

Y1 - 2009/1/15

N2 - Purpose: Despite objective response rates of only ∼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. Experimental Design: Using a panel of 26 human melanoma-derived cell lines, we determined in vitro temozolomide sensitivity, O 6-methylguanine-DNA methyltransferase (MGMT) activity, MGMT 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 μmol/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 ≤ 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.

AB - Purpose: Despite objective response rates of only ∼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. Experimental Design: Using a panel of 26 human melanoma-derived cell lines, we determined in vitro temozolomide sensitivity, O 6-methylguanine-DNA methyltransferase (MGMT) activity, MGMT 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 μmol/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 ≤ 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.

UR - http://www.scopus.com/inward/record.url?scp=59449085721&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=59449085721&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-08-1916

DO - 10.1158/1078-0432.CCR-08-1916

M3 - Article

VL - 15

SP - 502

EP - 510

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 2

ER -