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Analysis of Lymph Node Volume by Ultra-High-Frequency Ultrasound Imaging in the Braf/Pten Genetically Engineered Mouse Model of Melanoma
Published on: September 8, 2021
BRAF V600-Mutated Metastatic Melanoma and Targeted Therapy Resistance: An Update of the Current Knowledge
Laetitia Florent1, Charles Saby1, Florian Slimano1,2
1Université de Reims Champagne-Ardenne, UFR de Pharmacie, BioSpecT EA 7506, 51097 Reims, France.
Abstract:
Melanoma is the most common cause of death in skin cancer due to its high metastatic potential. While targeted therapies have improved the care of patients with metastatic melanoma harboring the BRAFV600E mutation, these treatments are associated with a high frequency of resistance. Resistance factors are related to cellular adaptation as well as to changes in the tumor microenvironment. At the cellular level, resistance involves mutations, overexpression, activation, or inhibition of effectors involved in cell signaling pathways such as MAPK, PI3K/AKT, MITF, and epigenetic factors (miRNAs). In addition, several components of the melanoma microenvironment, such as soluble factors, collagen, and stromal cells also play a crucial role in this resistance. In fact, extracellular matrix remodeling impacts the physical and chemical properties with changes in the stiffness and acidity, respectively of the microenvironment. The cellular and immune components of the stroma are also affected, including immune cells and CAF. The aim of this manuscript is to review the mechanisms responsible for resistance to targeted therapies in BRAFV600E-mutated metastatic melanoma.
Insights
Targeted therapies for BRAFV600E metastatic melanoma face resistance due to cellular changes and tumor microenvironment alterations. Understanding these resistance mechanisms is key to improving patient outcomes in advanced skin cancer.
Area of Science:
- Oncology
- Dermatology
- Molecular Biology
Background:
- Melanoma is a deadly skin cancer with high metastatic potential.
- Targeted therapies for BRAFV600E-mutated melanoma improve care but often encounter resistance.
- Resistance mechanisms involve cellular adaptations and tumor microenvironment changes.
Purpose of the Study:
- To review the mechanisms of resistance to targeted therapies in BRAFV600E-mutated metastatic melanoma.
- To highlight the roles of cellular signaling pathways and the tumor microenvironment in therapeutic resistance.
Main Methods:
- Literature review of cellular and microenvironmental resistance factors.
- Analysis of signaling pathways (MAPK, PI3K/AKT, MITF) and epigenetic factors (miRNAs).
- Examination of tumor microenvironment components including extracellular matrix, stromal cells, and immune cells.
Main Results:
- Cellular resistance mechanisms include mutations, overexpression, or altered activity of key signaling molecules.
- Tumor microenvironment factors, such as altered matrix stiffness and acidity, contribute significantly to resistance.
- Stromal cells, including cancer-associated fibroblasts (CAFs) and immune cells, play a role in mediating resistance.
Conclusions:
- Resistance to targeted melanoma therapy is multifactorial, involving both intrinsic cellular changes and extrinsic microenvironmental influences.
- Further research into these complex interactions is crucial for developing strategies to overcome resistance and enhance treatment efficacy.
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