title: Activity of dasatinib against L576P KIT mutant melanoma: molecular, cellular, and clinical correlates.
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 ( 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.
authors: Department of Melanoma Medical Oncology and Department of Systems Biology, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Scott E
authors: SE
authors: Woodman
authors: Jonathan C
authors: JC
authors: Trent
authors: Katherine
authors: K
authors: Stemke-Hale
authors: Alexander J
authors: AJ
authors: Lazar
authors: Sabrina
authors: S
authors: Pricl
authors: Giovanni M
authors: GM
authors: Pavan
authors: Maurizio
authors: M
authors: Fermeglia
authors: Y N Vashisht
authors: YN
authors: Gopal
authors: Dan
authors: D
authors: Yang
authors: Donald A
authors: DA
authors: Podoloff
authors: Doina
authors: D
authors: Ivan
authors: Kevin B
authors: KB
authors: Kim
authors: Nicholas
authors: N
authors: Papadopoulos
authors: Patrick
authors: P
authors: Hwu
authors: Gordon B
authors: GB
authors: Mills
authors: Michael A
authors: MA
authors: Davies
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001483:Base Sequence; D001549:Benzamides; D045744:Cell Line, Tumor; D002470:Cell Survival; D000069439:Dasatinib; D006801:Humans; D000068877:Imatinib Mesylate; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D010879:Piperazines / Q000494:pharmacology; D017354:Point Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D000069439:Dasatinib