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Updated: May 6, 2026
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
Differential AKT dependency displayed by mouse models of BRAFV600E-initiated melanoma
Abstract:
Malignant melanoma is frequently driven by mutational activation of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) accompanied by silencing of the phosphatase and tensin homology (PTEN) tumor suppressor. Despite the implied importance of PI3K signaling in PTENNull melanomas, mutational activation of the gene encoding the catalytic subunit of PI3Kα (PIK3CA), is rarely detected. Since PTEN has both PI3-lipid phosphatase-dependent and -independent tumor suppressor activities, we investigated the contribution of PI3K signaling to BRAFV600E-induced melanomagenesis using mouse models, cultured melanoma cells, and PI3K pathway-targeted inhibitors. These experiments revealed that mutationally activated PIK3CAH1047R cooperates with BRAFV600E for melanomagenesis in mice. Moreover, pharmacological inhibition of PI3Ks prevented growth of BRAFV600E/PTENNull melanomas in vivo and in tissue culture. Combined inhibition of BRAFV600E and PI3K had more potent effects on the regression of established BRAFV600E/PTENNull melanomas and cultured melanoma cells than individual blockade of either pathway. Surprisingly, growth of BRAFV600E/PIK3CAH1047R melanomas was dependent on the protein kinase AKT; however, AKT inhibition had no effect on growth of BRAFV600E/PTENNull melanomas. These data indicate that PTEN silencing contributes a PI3K-dependent, but AKT-independent, function in melanomagenesis. Our findings enhance our knowledge of how BRAFV600E and PI3K signaling cooperate in melanomagenesis and provide preclinical validation for combined pathway-targeted inhibition of PI3K and BRAFV600E in the therapeutic management of BRAFV600E/PTENNull melanomas.
Insights
Targeting both BRAFV600E and PI3K pathways shows promise for treating BRAFV600E/PTENNull melanomas. PTEN loss impacts PI3K signaling independently of AKT, offering new therapeutic insights.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Malignant melanoma often involves BRAFV600E mutations and PTEN tumor suppressor silencing.
- PI3K signaling is crucial in PTEN-null melanomas, yet PIK3CA mutations are infrequent.
- PTEN exhibits both PI3-lipid phosphatase-dependent and -independent tumor suppressor functions.
Purpose of the Study:
- To investigate the role of PI3K signaling in BRAFV600E-driven melanomagenesis.
- To explore the cooperative effects of BRAFV600E and PIK3CA mutations.
- To evaluate the efficacy of combined BRAFV600E and PI3K inhibition in preclinical melanoma models.
Main Methods:
- Utilized mouse models and cultured melanoma cells.
- Employed PI3K pathway-targeted inhibitors.
- Assessed the impact of BRAFV600E, PIK3CAH1047R, and PTEN status on tumor growth and response to inhibitors.
Main Results:
- Mutationally activated PIK3CAH1047R cooperated with BRAFV600E in murine melanomagenesis.
- Pharmacological PI3K inhibition suppressed BRAFV600E/PTENNull melanoma growth in vitro and in vivo.
- Combined BRAFV600E and PI3K inhibition demonstrated superior efficacy in melanoma regression compared to single-agent blockade.
- BRAFV600E/PIK3CAH1047R melanoma growth was AKT-dependent, whereas BRAFV600E/PTENNull melanoma growth was AKT-independent but PI3K-dependent.
Conclusions:
- PTEN loss contributes a PI3K-dependent, AKT-independent function to melanomagenesis.
- BRAFV600E and PI3K signaling pathways cooperate significantly in melanoma development.
- Combined PI3K and BRAFV600E pathway inhibition offers a promising therapeutic strategy for BRAFV600E/PTENNull melanomas.
