RT Journal Article
SR Electronic
T1 Activity of dasatinib against <em>L576P KIT</em> mutant melanoma: Molecular, cellular, and clinical correlates
JF Molecular Cancer Therapeutics
JO Mol Cancer Ther
FD American Association for Cancer Research
SP 2079
OP 2085
DO 10.1158/1535-7163.MCT-09-0459
VO 8
IS 8
A1 Woodman, Scott E.
A1 Trent, Jonathan C.
A1 Stemke-Hale, Katherine
A1 Lazar, Alexander J.
A1 Pricl, Sabrina
A1 Pavan, Giovanni M.
A1 Fermeglia, Maurizio
A1 Gopal, Y.N. Vashisht
A1 Yang, Dan
A1 Podoloff, Donald A.
A1 Ivan, Doina
A1 Kim, Kevin B.
A1 Papadopoulos, Nicholas
A1 Hwu, Patrick
A1 Mills, Gordon B.
A1 Davies, Michael A.
YR 2009
UL http://mct.aacrjournals.org/content/8/8/2079.abstract
AB 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 (&gt;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. [Mol Cancer Ther 2009;8(8):2079–85]