Sorafenib, a multikinase inhibitor, enhances the response of melanoma to regional chemotherapy

Christina K. Augustine, Hiroaki Toshimitsu, Sin Ho Jung, Patricia A. Zipfel, Jin S. Yoo, Yasunori Yoshimoto, M. Angelica Selim, James Burchette, Georgia M. Beasley, Nicole McMahon, James Padussis, Scott K. Pruitt, Francis Ali-Osman, Douglas Tyler

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Melanoma responds poorly to standard chemotherapy due to its intrinsic chemoresistance. Multiple genetic and molecular defects, including an activating mutation in the BRaf kinase gene, are associated with melanoma, and the resulting alterations in signal transduction pathways regulating proliferation and apoptosis are thought to contribute to its chemoresistance. Sorafenib, a multikinase inhibitor that targets BRaf kinase, is Food and Drug Administration approved for use in advanced renal cell and hepatocellular carcinomas. Although sorafenib has shown little promise as a single agent in melanoma patients, recent clinical trials suggest that, when combined with chemotherapy, it may have more benefit. We evaluated the ability of sorafenib to augment the cytotoxic effects of melphalan, a regional chemotherapeutic agent, and temozolomide, used in systemic and regional treatment of melanoma, on a panel of 24 human melanoma-derived cell lines and in an animal model of melanoma. Marked differences in response to 10 μmol/L sorafenib alone were observed in vitro across cell lines. Response to sorafenib significantly correlated with extracellular signal-regulated kinase (ERK) downregulation and loss of Mcl-1 expression (P < 0.05). Experiments with the mitogen-activated protein kinase/ERK kinase inhibitor U0126 suggest a unique role for ERK downregulation in the observed effects. Sorafenib in combination with melphalan or temozolomide led to significantly improved responses in vitro (P < 0.05). In the animal model of melanoma, sorafenib in combination with regional melphalan or regional temozolomide was more effective than either treatment alone in slowing tumor growth. These results show that sorafenib in combination with chemotherapy provides a novel approach to enhance chemotherapeutic efficacy in the regional treatment of in-transit melanoma.

Original languageEnglish (US)
Pages (from-to)2090-2101
Number of pages12
JournalMolecular Cancer Therapeutics
Volume9
Issue number7
DOIs
StatePublished - 2010
Externally publishedYes

Fingerprint

Melanoma
temozolomide
Drug Therapy
Melphalan
Extracellular Signal-Regulated MAP Kinases
Phosphotransferases
Down-Regulation
Animal Models
Cell Line
sorafenib
United States Food and Drug Administration
Mitogen-Activated Protein Kinases
Combination Drug Therapy
Renal Cell Carcinoma
Molecular Biology
Hepatocellular Carcinoma
Signal Transduction
Therapeutics
Clinical Trials
Apoptosis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Medicine(all)

Cite this

Sorafenib, a multikinase inhibitor, enhances the response of melanoma to regional chemotherapy. / Augustine, Christina K.; Toshimitsu, Hiroaki; Jung, Sin Ho; Zipfel, Patricia A.; Yoo, Jin S.; Yoshimoto, Yasunori; Selim, M. Angelica; Burchette, James; Beasley, Georgia M.; McMahon, Nicole; Padussis, James; Pruitt, Scott K.; Ali-Osman, Francis; Tyler, Douglas.

In: Molecular Cancer Therapeutics, Vol. 9, No. 7, 2010, p. 2090-2101.

Research output: Contribution to journalArticle

Augustine, CK, Toshimitsu, H, Jung, SH, Zipfel, PA, Yoo, JS, Yoshimoto, Y, Selim, MA, Burchette, J, Beasley, GM, McMahon, N, Padussis, J, Pruitt, SK, Ali-Osman, F & Tyler, D 2010, 'Sorafenib, a multikinase inhibitor, enhances the response of melanoma to regional chemotherapy', Molecular Cancer Therapeutics, vol. 9, no. 7, pp. 2090-2101. https://doi.org/10.1158/1535-7163.MCT-10-0073
Augustine, Christina K. ; Toshimitsu, Hiroaki ; Jung, Sin Ho ; Zipfel, Patricia A. ; Yoo, Jin S. ; Yoshimoto, Yasunori ; Selim, M. Angelica ; Burchette, James ; Beasley, Georgia M. ; McMahon, Nicole ; Padussis, James ; Pruitt, Scott K. ; Ali-Osman, Francis ; Tyler, Douglas. / Sorafenib, a multikinase inhibitor, enhances the response of melanoma to regional chemotherapy. In: Molecular Cancer Therapeutics. 2010 ; Vol. 9, No. 7. pp. 2090-2101.
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AU - Yoshimoto, Yasunori

AU - Selim, M. Angelica

AU - Burchette, James

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AU - McMahon, Nicole

AU - Padussis, James

AU - Pruitt, Scott K.

AU - Ali-Osman, Francis

AU - Tyler, Douglas

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