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|Ref Type||Journal Article|
|Authors||Woodman SE, Trent JC, Stemke-Hale K, Lazar AJ, Pricl S, Pavan GM, Fermeglia M, Gopal YN, Yang D, Podoloff DA, Ivan D, Kim KB, Papadopoulos N, Hwu P, Mills GB, Davies MA|
|Title||Activity of dasatinib against L576P KIT mutant melanoma: molecular, cellular, and clinical correlates.|
|Journal||Molecular cancer therapeutics|
|Abstract Text||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 ( approximately 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 (DeltaDeltaGbind = -2.52 kcal/mol) but not for dasatinib (DeltaDeltaGbind = +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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|KIT L576P||melanoma||sensitive||Dasatinib||Case Reports/Case Series||Actionable||In a clinical study, two patients with melanoma harboring KIT L576P, one who had progressed on Gleevec (imatinib), demonstrated initial clinical benefit following treatment with Sprycel (dasatinib); however, one patient progressed after 3 months, and the other patient progressed after 4 months of treatment (PMID: 19671763).||19671763|