Activity of dasatinib against L576P KIT mutant melanoma: Molecular, cellular, and clinical correlates

Scott E. Woodman, Jonathan C. Trent, Katherine Stemke-Hale, Alexander J. Lazar, Sabrina Pricl, Giovanni M. Pavan, Maurizio Fermeglia, Y. N.Vashisht Gopal, Dan Yang, Donald A. Podoloff, Doina Ivan, Kevin B. Kim, Nicholas Papadopoulos, Patrick Hwu, Gordon B. Mills, Michael A. Davies

    Research output: Contribution to journalArticle

    138 Scopus citations

    Abstract

    Point mutations in the KIT receptor tyrosine kinase gene have recently been identified in mucosal, acral lentiginous, and chronically sun-damaged melanomas. We have identified the first human melanoma cell line with an endogenous L576P mutation, the most common KIT mutation in melanoma ( 30-40%). In vitro testing showed that the cell viability of the L576P mutant cell line was not reduced by imatinib, nilotinib, or sorafenib small molecule KIT inhibitors effective in nonmelanoma cells with other KIT mutations. However, the viability of the mutant cells was reduced by dasatinib at concentrations as low as 10 nM (P = 0.004). Molecular modeling studies found that the L576P mutation induces structural changes in KIT that reduce the affinity for imatinib (ΔΔGbind = -2.52 kcal/mol) but not for dasatinib (ΔΔGbind = +0.32 kcal/mol). Two metastatic melanoma patients with the L576P KIT mutation were treated with dasatinib, including one patient previously treated with imatinib. Both patients had marked reduction (>50%) and elimination of tumor F18-fluorodeoxyglucose (FDG)-avidity by positron emission tomography (PET) imaging after dasatinib treatment. These data support the selective inhibitory effect of dasatinib against cells harboring the most common KIT mutation in melanoma, and thus has therapeutic implications for acrallentiginous, chronic sun-damaged, and mucosal melanomas.

    Original languageEnglish (US)
    Pages (from-to)2079-2085
    Number of pages7
    JournalMolecular cancer therapeutics
    Volume8
    Issue number8
    DOIs
    StatePublished - Aug 1 2009

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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  • Cite this

    Woodman, S. E., Trent, J. C., Stemke-Hale, K., Lazar, A. J., Pricl, S., Pavan, G. M., Fermeglia, M., Gopal, Y. N. V., Yang, D., Podoloff, D. A., Ivan, D., Kim, K. B., Papadopoulos, N., Hwu, P., Mills, G. B., & Davies, M. A. (2009). Activity of dasatinib against L576P KIT mutant melanoma: Molecular, cellular, and clinical correlates. Molecular cancer therapeutics, 8(8), 2079-2085. https://doi.org/10.1158/1535-7163.MCT-09-0459