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

Woodman, Scott E. and Trent, Jonathan C. and Stemke-Hale, Katherine and Lazar, Alexander J. and Pricl, Sabrina and Pavan, Giovanni Maria and Fermeglia, Maurizio and Gopal, Y.N. Vashisht and Yang, Dan and Podoloff, Donald A. and Ivan, Doina and Kim, Kevin B. and Papadopulos, Nicholas and Hwu, Patrick and Mills, Gordon B. and Davies, Michael A. (2009) Activity of dasatinib against L576P KIT mutant melanoma: molecular, cellular, and clinical correlates. Molecular cancer therapeutics, 8 (8). pp. 2079-2085. ISSN 1535-7163

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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 demonstrated that the cell viability of the L576P mutant cell line was not reduced by imatinib, nilotinib or sorafenib small molecule KIT inhibitors effective in non-melanoma 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 FDG-avidity by PET imaging after dasatinib treatment. This data supports the selective inhibitory effect of dasatinib against cells harboring the most common KIT mutation in melanoma, and thus has therapeutic implications for acral lentiginous, chronic sun damaged, and mucosal melanomas.

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