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SRC family kinase inhibition as a novel strategy to augment melphalan-based regional chemotherapy of advanced extremity melanoma.

Publication ,  Journal Article
Tokuhisa, Y; Lidsky, ME; Toshimitsu, H; Turley, RS; Beasley, GM; Ueno, T; Sharma, K; Augustine, CK; Tyler, DS
Published in: Ann Surg Oncol
March 2014

BACKGROUND: Src kinase inhibition has been shown to augment the efficacy of chemotherapy. Dasatinib, a dual Src/Abl kinase inhibitor approved for the treatment of CML, is under investigation as monotherapy for tumors with abnormal Src signaling, such as melanoma. The goal of this study was to determine if Src kinase inhibition using dasatinib could enhance the efficacy of regionally administered melphalan in advanced extremity melanoma. METHODS: The mutational status of c-kit and patterns of gene expression predictive of dysregulated Src kinase signaling were evaluated in a panel of 26 human melanoma cell lines. The effectiveness of dasatinib was measured by quantifying protein expression and activation of Src kinase, focal adhesion kinase, and Crk-associated substrate (p130(CAS)), in conjunction with in vitro cell viability assays using seven melanoma cell lines. Utilizing a rat model of regional chemotherapy, we evaluated the effectiveness of systemic dasatinib in conjunction with regional melphalan against the human melanoma cell line, DM443, grown as a xenograft. RESULTS: Only the WM3211 cell line harbored a c-kit mutation. Significant correlation was observed between Src-predicted dysregulation by gene expression and sensitivity to dasatinib in vitro. Tumor doubling time for DM443 xenografts treated with systemic dasatinib in combination with regional melphalan (44.8 days) was significantly longer (p = 0.007) than either dasatinib (21.3 days) or melphalan alone (24.7 days). CONCLUSIONS: Systemic dasatinib prior to melphalan-based regional chemotherapy markedly improves the efficacy of this alkylating agent in this melanoma xenograft model. Validation of this concept should be considered in the context of a regional therapy clinical trial.

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Published In

Ann Surg Oncol

DOI

EISSN

1534-4681

Publication Date

March 2014

Volume

21

Issue

3

Start / End Page

1024 / 1030

Location

United States

Related Subject Headings

  • src-Family Kinases
  • Xenograft Model Antitumor Assays
  • Tumor Cells, Cultured
  • Thiazoles
  • Real-Time Polymerase Chain Reaction
  • Rats, Nude
  • Rats
  • Pyrimidines
  • Proto-Oncogene Proteins c-kit
  • Protein Kinase Inhibitors
 

Citation

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Tokuhisa, Y., Lidsky, M. E., Toshimitsu, H., Turley, R. S., Beasley, G. M., Ueno, T., … Tyler, D. S. (2014). SRC family kinase inhibition as a novel strategy to augment melphalan-based regional chemotherapy of advanced extremity melanoma. Ann Surg Oncol, 21(3), 1024–1030. https://doi.org/10.1245/s10434-013-3387-6
Tokuhisa, Yoshihiro, Michael E. Lidsky, Hiroaki Toshimitsu, Ryan S. Turley, Georgia M. Beasley, Tomio Ueno, Ketan Sharma, Christina K. Augustine, and Douglas S. Tyler. “SRC family kinase inhibition as a novel strategy to augment melphalan-based regional chemotherapy of advanced extremity melanoma.Ann Surg Oncol 21, no. 3 (March 2014): 1024–30. https://doi.org/10.1245/s10434-013-3387-6.
Tokuhisa Y, Lidsky ME, Toshimitsu H, Turley RS, Beasley GM, Ueno T, et al. SRC family kinase inhibition as a novel strategy to augment melphalan-based regional chemotherapy of advanced extremity melanoma. Ann Surg Oncol. 2014 Mar;21(3):1024–30.
Tokuhisa, Yoshihiro, et al. “SRC family kinase inhibition as a novel strategy to augment melphalan-based regional chemotherapy of advanced extremity melanoma.Ann Surg Oncol, vol. 21, no. 3, Mar. 2014, pp. 1024–30. Pubmed, doi:10.1245/s10434-013-3387-6.
Tokuhisa Y, Lidsky ME, Toshimitsu H, Turley RS, Beasley GM, Ueno T, Sharma K, Augustine CK, Tyler DS. SRC family kinase inhibition as a novel strategy to augment melphalan-based regional chemotherapy of advanced extremity melanoma. Ann Surg Oncol. 2014 Mar;21(3):1024–1030.

Published In

Ann Surg Oncol

DOI

EISSN

1534-4681

Publication Date

March 2014

Volume

21

Issue

3

Start / End Page

1024 / 1030

Location

United States

Related Subject Headings

  • src-Family Kinases
  • Xenograft Model Antitumor Assays
  • Tumor Cells, Cultured
  • Thiazoles
  • Real-Time Polymerase Chain Reaction
  • Rats, Nude
  • Rats
  • Pyrimidines
  • Proto-Oncogene Proteins c-kit
  • Protein Kinase Inhibitors