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Published on: July 8, 2020
KIT in melanoma: many shades of gray
Ana Slipicevic1, Meenhard Herlyn2
1Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, Pennsylvania, USA; Department of Pathology, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway.
Abstract:
Activating mutations in KIT have been identified in melanomas of acral and mucosal types and in those arising in chronically sun-damaged skin. Until now, KIT has been considered an oncogenic driver and a potential therapeutic target. However, data presented by Dhal et al. show that in cutaneous melanomas the KIT promoter is a target for hypermethylation, leading to its downregulation. Their observations suggest that signaling pathways downstream of KIT may have distinct and opposing roles in the pathogenesis of melanoma subtypes. This will have important implications for the use of KIT inhibitors in treating melanomas.
Insights
KIT mutations drive some melanomas, but new research shows KIT promoter hypermethylation downregulates KIT in cutaneous melanomas. This suggests complex roles for KIT signaling in different melanoma subtypes, impacting KIT inhibitor therapies.
Area of Science:
- Oncology
- Dermatology
- Molecular Biology
Background:
- Activating mutations in the KIT proto-oncogene have been implicated in melanoma pathogenesis, particularly in acral, mucosal, and chronically sun-damaged skin subtypes.
- KIT has been regarded as a significant oncogenic driver and a potential therapeutic target in melanoma treatment.
Purpose of the Study:
- To investigate the role of KIT in cutaneous melanoma beyond activating mutations.
- To explore the epigenetic regulation of KIT in melanoma.
- To understand the implications of KIT's role in melanoma subtype-specific pathogenesis and therapeutic strategies.
Main Methods:
- Analysis of KIT promoter methylation status in cutaneous melanoma samples.
- Assessment of KIT gene expression levels.
- Evaluation of downstream signaling pathway activity.
Main Results:
- The KIT promoter is a target for hypermethylation in cutaneous melanomas, leading to reduced KIT expression.
- Downregulation of KIT through hypermethylation suggests a different role compared to activating mutations in other melanoma types.
- Signaling pathways downstream of KIT may exhibit distinct and opposing functions in various melanoma subtypes.
Conclusions:
- KIT's role in melanoma is complex and subtype-dependent, involving both activating mutations and epigenetic downregulation.
- Hypermethylation of the KIT promoter represents a key mechanism in a subset of cutaneous melanomas.
- These findings necessitate a re-evaluation of KIT inhibitor efficacy across different melanoma subtypes.
