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Updated: Mar 26, 2026
A 3D Organotypic Melanoma Spheroid Skin Model
Published on: May 18, 2018
Enhancing the evaluation of PI3K inhibitors through 3D melanoma models
Batool Shannan1,2, Quan Chen1, Andrea Watters1
1Program of Cellular and Molecular Oncogenesis, Melanoma Research Center, The Wistar Institute, Philadelphia, PA, USA.
Abstract:
Targeted therapies for mutant BRAF metastatic melanoma are effective but not curative due to acquisition of resistance. PI3K signaling is a common mediator of therapy resistance in melanoma; thus, the need for effective PI3K inhibitors is critical. However, testing PI3K inhibitors in adherent cultures is not always reflective of their potential in vivo. To emphasize this, we compared PI3K inhibitors of different specificity in two- and three-dimensional (2D, 3D) melanoma models and show that drug response predictions gain from evaluation using 3D models. Our results in 3D demonstrate the anti-invasive potential of PI3K inhibitors and that drugs such as PX-866 have beneficial activity in physiological models alone and when combined with BRAF inhibition. These assays finally help highlight pathway effectors that could be involved in drug response in different environments (e.g. p4E-BP1). Our findings show the advantages of 3D melanoma models to enhance our understanding of PI3K inhibitors.
Insights
Three-dimensional (3D) melanoma models reveal the anti-invasive potential of phosphoinositide 3-kinase (PI3K) inhibitors, improving predictions of drug response and combination therapies for metastatic melanoma.
Area of Science:
- Oncology
- Melanoma Research
- Drug Discovery
Background:
- Targeted therapies for BRAF-mutant melanoma face curative limitations due to acquired resistance.
- Phosphoinositide 3-kinase (PI3K) signaling is a key mediator of therapeutic resistance in melanoma.
- Standard 2D cell cultures may not accurately predict in vivo drug efficacy for PI3K inhibitors.
Purpose of the Study:
- To evaluate the utility of 3D melanoma models for assessing PI3K inhibitor efficacy.
- To compare PI3K inhibitor responses in 2D versus 3D culture systems.
- To identify potential therapeutic strategies combining PI3K inhibition with BRAF inhibition.
Main Methods:
- Comparison of PI3K inhibitors with varying specificities in 2D and 3D melanoma models.
- Assessment of drug response and anti-invasive potential in different dimensional models.
- Analysis of pathway effectors, such as phosphorylated 4E-binding protein 1 (p4E-BP1), in response to treatment.
Main Results:
- Three-dimensional models provide more accurate predictions of PI3K inhibitor response compared to 2D models.
- PI3K inhibitors demonstrated significant anti-invasive activity in 3D melanoma models.
- The drug PX-866 showed beneficial effects alone and in combination with BRAF inhibition in physiological models.
- Identification of pathway effectors like p4E-BP1 involved in drug response across different cellular environments.
Conclusions:
- Three-dimensional melanoma models are advantageous for understanding PI3K inhibitor mechanisms and predicting clinical outcomes.
- Evaluating PI3K inhibitors in 3D cultures enhances the understanding of their anti-invasive properties.
- The findings support the use of 3D models for optimizing targeted therapy and combination strategies in metastatic melanoma.
