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Src Family Kinase Inhibition as a Novel Strategy to Augment Melphalan-Based Regional Chemotherapy of Advanced Extremity Melanoma

  • Melanomas
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

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 (p130CAS), 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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Acknowledgment

Duke Melanoma Research Fund (D.S. Tyler), and a VA Merit Review Grant (D.S. Tyler).

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Authors and Affiliations

  1. Department of Surgery, Duke University Medical Center, Durham, NC, USA

    Yoshihiro Tokuhisa MD, PhD, Michael E. Lidsky MD, Hiroaki Toshimitsu MD, PhD, Ryan S. Turley MD, Georgia M. Beasley MD, Ketan Sharma MD, Christina K. Augustine PhD & Douglas S. Tyler MD

  2. Department of Surgery, Durham VA Medical Center, Durham, NC, USA

    Yoshihiro Tokuhisa MD, PhD, Hiroaki Toshimitsu MD, PhD, Christina K. Augustine PhD & Douglas S. Tyler MD

  3. Department of Digestive Surgery and Surgical Oncology, Yamaguchi University School of Medicine, Yamaguchi, Japan

    Tomio Ueno MD

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  1. Yoshihiro Tokuhisa MD, PhD
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  2. Michael E. Lidsky MD
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  3. Hiroaki Toshimitsu MD, PhD
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  4. Ryan S. Turley MD
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  5. Georgia M. Beasley MD
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  8. Christina K. Augustine PhD
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  9. Douglas S. Tyler MD
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Corresponding author

Correspondence to Michael E. Lidsky MD.

Additional information

Yoshihiro Tokuhisa and Michael E. Lidsky have contributed equally to this work.

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Tokuhisa, Y., Lidsky, M.E., Toshimitsu, H. et al. Src Family Kinase Inhibition as a Novel Strategy to Augment Melphalan-Based Regional Chemotherapy of Advanced Extremity Melanoma. Ann Surg Oncol 21, 1024–1030 (2014). https://doi.org/10.1245/s10434-013-3387-6

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  • DOI: https://doi.org/10.1245/s10434-013-3387-6

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