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Published on: May 18, 2018
Identification of a novel subgroup of melanomas with KIT/cyclin-dependent kinase-4 overexpression
Keiran S M Smalley1, Rooha Contractor, Thiennga K Nguyen
1The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA. K.smalley@mac.com
Abstract:
Although many melanomas harbor either activating mutations in BRAF or NRAS, there remains a substantial, yet little known, group of tumors without either mutation. Here, we used a genomic strategy to define a novel group of melanoma cell lines with co-overexpression of cyclin-dependent kinase 4 (CDK4) and KIT. Although this subgroup lacked any known KIT mutations, they had high phospho-KIT receptor expression, indicating receptor activity. Quantitative PCR confirmed the existence of a similar KIT/CDK4 subgroup in human melanoma samples. Pharmacologic studies showed the KIT/CDK4-overexpressing subgroup to be resistant to BRAF inhibitors but sensitive to imatinib in both in vitro and in vivo melanoma models. Mechanistically, imatinib treatment led to increased apoptosis and G(1) phase cell cycle arrest associated with the inhibition of phospho-ERK and increased expression of p27(KIP). Other melanoma cell lines, which retained some KIT expression but lacked phospho-KIT, were not sensitive to imatinib, suggesting that KIT expression alone is not predictive of response. We suggest that co-overexpression of KIT/CDK4 is a potential mechanism of oncogenic transformation in some BRAF/NRAS wild-type melanomas. This group of melanomas may be a subpopulation for which imatinib or other KIT inhibitors may constitute optimal therapy.
Insights
A novel melanoma subgroup overexpressing KIT and cyclin-dependent kinase 4 (CDK4) lacks BRAF/NRAS mutations. These tumors are sensitive to imatinib, suggesting KIT inhibitors as a potential therapy for this BRAF/NRAS wild-type melanoma subset.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Many melanomas harbor BRAF or NRAS mutations.
- A subset of melanomas lacks these common mutations, indicating alternative oncogenic drivers.
- Understanding these alternative pathways is crucial for developing targeted therapies.
Purpose of the Study:
- To identify novel molecular subgroups within BRAF/NRAS wild-type melanomas.
- To investigate the role of KIT and CDK4 co-overexpression in melanoma pathogenesis.
- To evaluate the therapeutic potential of imatinib in this specific melanoma subtype.
Main Methods:
- Genomic analysis to identify novel melanoma cell lines.
- Quantitative PCR to confirm gene expression in human samples.
- Pharmacologic studies using BRAF inhibitors and imatinib in vitro and in vivo.
- Analysis of apoptosis, cell cycle arrest, and downstream signaling pathways.
Main Results:
- A novel melanoma subgroup characterized by KIT and CDK4 co-overexpression was identified.
- This subgroup, lacking KIT mutations but showing high phospho-KIT, was resistant to BRAF inhibitors.
- KIT/CDK4-overexpressing melanomas demonstrated sensitivity to imatinib, with increased apoptosis and G1 cell cycle arrest.
- Phospho-ERK inhibition and p27(KIP) upregulation were observed upon imatinib treatment.
- KIT expression alone, without phospho-KIT, did not predict imatinib sensitivity.
Conclusions:
- Co-overexpression of KIT and CDK4 represents a potential oncogenic mechanism in BRAF/NRAS wild-type melanomas.
- This specific melanoma subpopulation may benefit from imatinib or other KIT inhibitors.
- Targeting KIT signaling offers a therapeutic strategy for a subset of melanomas currently lacking effective targeted treatments.
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