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

Publication ,  Journal Article
Augustine, CK; Toshimitsu, H; Jung, S-H; Zipfel, PA; Yoo, JS; Yoshimoto, Y; Selim, MA; Burchette, J; Beasley, GM; McMahon, N; Padussis, J ...
Published in: Mol Cancer Ther
July 2010

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 micromol/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.

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Published In

Mol Cancer Ther

DOI

EISSN

1538-8514

Publication Date

July 2010

Volume

9

Issue

7

Start / End Page

2090 / 2101

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Burden
  • Temozolomide
  • Sorafenib
  • Rats, Nude
  • Rats
  • Pyridines
  • Proto-Oncogene Proteins c-bcl-2
  • Proto-Oncogene Proteins B-raf
  • Protein Kinase Inhibitors
 

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Augustine, C. K., Toshimitsu, H., Jung, S.-H., Zipfel, P. A., Yoo, J. S., Yoshimoto, Y., … Tyler, D. S. (2010). Sorafenib, a multikinase inhibitor, enhances the response of melanoma to regional chemotherapy. Mol Cancer Ther, 9(7), 2090–2101. https://doi.org/10.1158/1535-7163.MCT-10-0073
Augustine, Christina K., Hiroaki Toshimitsu, Sin-Ho Jung, Patricia A. Zipfel, Jin S. Yoo, Yasunori Yoshimoto, M Angelica Selim, et al. “Sorafenib, a multikinase inhibitor, enhances the response of melanoma to regional chemotherapy.Mol Cancer Ther 9, no. 7 (July 2010): 2090–2101. https://doi.org/10.1158/1535-7163.MCT-10-0073.
Augustine CK, Toshimitsu H, Jung S-H, Zipfel PA, Yoo JS, Yoshimoto Y, et al. Sorafenib, a multikinase inhibitor, enhances the response of melanoma to regional chemotherapy. Mol Cancer Ther. 2010 Jul;9(7):2090–101.
Augustine, Christina K., et al. “Sorafenib, a multikinase inhibitor, enhances the response of melanoma to regional chemotherapy.Mol Cancer Ther, vol. 9, no. 7, July 2010, pp. 2090–101. Pubmed, doi:10.1158/1535-7163.MCT-10-0073.
Augustine CK, Toshimitsu H, Jung S-H, Zipfel PA, Yoo JS, Yoshimoto Y, Selim MA, Burchette J, Beasley GM, McMahon N, Padussis J, Pruitt SK, Ali-Osman F, Tyler DS. Sorafenib, a multikinase inhibitor, enhances the response of melanoma to regional chemotherapy. Mol Cancer Ther. 2010 Jul;9(7):2090–2101.

Published In

Mol Cancer Ther

DOI

EISSN

1538-8514

Publication Date

July 2010

Volume

9

Issue

7

Start / End Page

2090 / 2101

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Tumor Burden
  • Temozolomide
  • Sorafenib
  • Rats, Nude
  • Rats
  • Pyridines
  • Proto-Oncogene Proteins c-bcl-2
  • Proto-Oncogene Proteins B-raf
  • Protein Kinase Inhibitors