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FOXD1 promotes dedifferentiation and targeted therapy resistance in melanoma by regulating the expression of
Qian Sun1,2, Daniel Novak1,2, Laura Hüser1,2
1Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Abstract:
Metastatic melanoma is an aggressive skin cancer and associated with a poor prognosis. In clinical terms, targeted therapy is one of the most important treatments for patients with BRAFV600E -mutated advanced melanoma. However, the development of resistance to this treatment compromises its therapeutic success. We previously demonstrated that forkhead box D1 (FOXD1) regulates melanoma migration and invasion. Here, we found that FOXD1 was highly expressed in melanoma cells and was associated with a poor survival of patients with metastatic melanoma. Upregulation of FOXD1 expression enhanced melanoma cells' resistance to vemurafenib (BRAF inhibitor [BRAFi]) or vemurafenib and cobimetinib (MEK inhibitor) combination treatment whereas loss of FOXD1 increased the sensitivity to treatment. By comparing gene expression levels between FOXD1 knockdown (KD) and overexpressing (OE) cells, we identified the connective tissue growth factor (CTGF) as a downstream factor of FOXD1. Chromatin immunoprecipitation and luciferase assay demonstrated the direct binding of FOXD1 to the CTGF promoter. Similar to FOXD1, knockdown of CTGF increased the sensitivity of BRAFi-resistant cells to vemurafenib. FOXD1 KD cells treated with recombinant CTGF protein were less sensitive towards vemurafenib compared to untreated FOXD1 KD cells. Based on these findings, we conclude that FOXD1 might be a promising new diagnostic marker and a therapeutic target for the treatment of targeted therapy resistant melanoma.
Insights
Forkhead box D1 (FOXD1) drives resistance to targeted melanoma therapies. Targeting FOXD1 or its downstream factor, CTGF, may restore sensitivity to BRAF inhibitors in advanced melanoma.
Area of Science:
- Oncology
- Molecular Biology
- Dermatology
Background:
- Metastatic melanoma is an aggressive cancer with poor prognosis.
- Targeted therapy, like BRAF inhibitors, is crucial for BRAFV600E-mutated melanoma but faces resistance.
- Forkhead box D1 (FOXD1) has been implicated in melanoma cell migration and invasion.
Purpose of the Study:
- To investigate the role of FOXD1 in melanoma targeted therapy resistance.
- To identify downstream targets of FOXD1 involved in resistance mechanisms.
- To evaluate FOXD1 and its downstream targets as potential therapeutic strategies.
Main Methods:
- Gene expression analysis in melanoma cells.
- FOXD1 knockdown (KD) and overexpression (OE) models.
- Treatment with BRAF inhibitors (vemurafenib) and MEK inhibitors (cobimetinib).
- Chromatin immunoprecipitation and luciferase assays to confirm gene regulation.
- Connective tissue growth factor (CTGF) knockdown and recombinant protein treatment.
Main Results:
- FOXD1 expression is high in melanoma and associated with poor patient survival.
- Increased FOXD1 confers resistance to vemurafenib and combination therapy.
- Decreased FOXD1 enhances sensitivity to targeted therapy.
- CTGF is a direct downstream target of FOXD1.
- CTGF knockdown also increases sensitivity to vemurafenib in resistant cells.
Conclusions:
- FOXD1 promotes resistance to targeted therapy in metastatic melanoma.
- FOXD1 directly regulates CTGF expression.
- Both FOXD1 and CTGF are potential therapeutic targets to overcome treatment resistance.
- FOXD1 may serve as a diagnostic marker for targeted therapy resistance in melanoma.
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