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Updated: Jun 21, 2026
A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
Published on: December 7, 2014
Activity of dasatinib against L576P KIT mutant melanoma: molecular, cellular, and clinical correlates
Scott E Woodman1, Jonathan C Trent, Katherine Stemke-Hale
1Department of Melanoma Medical Oncology and Department of Systems Biology, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.
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.
Insights
Dasatinib effectively targets the common L576P KIT mutation in melanoma, unlike other inhibitors. This finding offers new therapeutic options for acral lentiginous, mucosal, and sun-damaged melanomas.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Point mutations in the KIT receptor tyrosine kinase gene are implicated in various melanoma subtypes.
- The L576P mutation is the most prevalent KIT mutation in melanoma, found in approximately 30-40% of cases.
Purpose of the Study:
- To investigate the efficacy of small molecule KIT inhibitors against the L576P mutation in melanoma.
- To evaluate dasatinib as a potential therapeutic agent for melanomas harboring the L576P KIT mutation.
Main Methods:
- Established and utilized a human melanoma cell line with an endogenous L576P KIT mutation.
- Performed in vitro drug sensitivity assays with imatinib, nilotinib, sorafenib, and dasatinib.
- Conducted molecular modeling studies to assess drug-target binding affinities.
- Administered dasatinib to two metastatic melanoma patients with the L576P mutation and monitored tumor response via PET imaging.
Main Results:
- The L576P mutant melanoma cell line showed resistance to imatinib, nilotinib, and sorafenib.
- Dasatinib demonstrated significant inhibition of L576P mutant cell viability at low concentrations (10 nM).
- Molecular modeling indicated reduced affinity of imatinib but not dasatinib to the mutated KIT.
- Both treated patients exhibited substantial tumor regression and reduced metabolic activity post-dasatinib therapy.
Conclusions:
- Dasatinib exhibits selective inhibitory activity against melanoma cells with the L576P KIT mutation.
- These findings support dasatinib's therapeutic potential for acral lentiginous, chronic sun-damaged, and mucosal melanomas.
- The study highlights the importance of targeted therapies based on specific KIT mutations in melanoma treatment.
