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Updated: Jan 20, 2026
Experimental Metastatic Melanoma Mouse Model: A Platform to Study the Metastatic Potential of Melanoma Cells in the Lungs
Published on: April 30, 2023
Effective Treatment of Metastatic Melanoma by Combining MAPK and PI3K Signaling Pathway Inhibitors
Synnøve Nymark Aasen1,2, Himalaya Parajuli1, Tuyen Hoang1
1Kristian Gerhard Jebsen Brain Tumour Research Centre, Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009 Bergen, Norway.
Abstract:
Malignant melanoma is the most aggressive type of skin cancer and is closely associated with the development of brain metastases. Despite aggressive treatment, the prognosis has traditionally been poor, necessitating improved therapies. In melanoma, the mitogen activated protein kinase and the phosphoinositide 3-kinase signaling pathways are commonly altered, and therapeutically inhibiting one of the pathways often upregulates the other, leading to resistance. Thus, combined treatment targeting both pathways is a promising strategy to overcome this. Here, we studied the in vitro and in vivo effects of the PI3K inhibitor buparlisib and the MEK1/2 inhibitor trametinib, used either as targeted monotherapies or in combination, on patient-derived melanoma brain metastasis cell lines. Scratch wound and trans-well assays were carried out to assess the migratory capacity of the cells upon drug treatment, whereas flow cytometry, apoptosis array and Western blots were used to study apoptosis. Finally, an in vivo treatment experiment was carried out on NOD/SCID mice. We show that combined therapy was more effective than monotherapy. Combined treatment also more effectively increased apoptosis, and inhibited tumor growth in vivo. This suggests a clinical potential of combined treatment to overcome ceased treatment activity which is often seen after monotherapies, and strongly encourages the evaluation of the treatment strategy on melanoma patients with brain metastases.
Insights
Combined therapy targeting both PI3K and MEK pathways shows promise for melanoma brain metastases. This dual-action approach effectively inhibits tumor growth and increases apoptosis, offering a potential new treatment strategy.
Area of Science:
- Oncology
- Dermatology
- Cancer Research
Background:
- Malignant melanoma is an aggressive skin cancer often metastasizing to the brain.
- Current treatments for melanoma brain metastases have limited efficacy, with poor prognosis.
- Signaling pathways like PI3K and MAPK are frequently altered in melanoma, leading to therapeutic resistance.
Purpose of the Study:
- To investigate the efficacy of combined PI3K and MEK inhibition in melanoma brain metastases.
- To evaluate the effects of buparlisib (PI3K inhibitor) and trametinib (MEK1/2 inhibitor) on melanoma cell migration and apoptosis.
- To assess the in vivo therapeutic potential of combination therapy in a mouse model.
Main Methods:
- In vitro studies using patient-derived melanoma brain metastasis cell lines.
- Scratch wound and trans-well assays to evaluate cell migration.
- Flow cytometry, apoptosis array, and Western blots to assess apoptosis.
- In vivo experiments utilizing NOD/SCID mice.
Main Results:
- Combined buparlisib and trametinib therapy demonstrated superior efficacy compared to monotherapy.
- Combination treatment significantly enhanced apoptosis in melanoma cells.
- In vivo studies showed that combined therapy effectively inhibited tumor growth in mice.
Conclusions:
- Combined PI3K and MEK inhibition is a promising strategy to overcome resistance in melanoma brain metastases.
- This combination therapy warrants further clinical evaluation for patients with melanoma brain metastases.
- The findings suggest potential to improve treatment outcomes by overcoming monotherapy resistance.
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