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Raptinal Induces Gasdermin E-Dependent Pyroptosis in Naïve and Therapy-Resistant Melanoma
Megane Vernon1, Nicole A Wilski1, Daniel Kotas1
1Department of Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.
Abstract:
Lack of response and acquired resistance continue to be limitations of targeted and immune-based therapies. Pyroptosis is an inflammatory form of cell death characterized by the release of inflammatory damage-associated molecular patterns (DAMP) and cytokines via gasdermin (GSDM) protein pores in the plasma membrane. Induction of pyroptosis has implications for treatment strategies in both therapy-responsive, as well as resistance forms of melanoma. We show that the caspase-3 activator, raptinal, induces pyroptosis in both human and mouse melanoma cell line models and delays tumor growth in vivo. Release of DAMPs and inflammatory cytokines was dependent on caspase activity and GSDME expression. Furthermore, raptinal stimulated pyroptosis in melanoma models that have acquired resistance to BRAF and MEK inhibitor therapy. These findings add support to efforts to induce pyroptosis in both the treatment-naïve and resistant settings.
Implications:
Raptinal can rapidly induce pyroptosis in naïve and BRAFi plus MEKi-resistant melanoma, which may be beneficial for patients who have developed acquired resistance to targeted therapies.
Insights
Raptinal, a pyroptosis inducer, shows promise in treating melanoma, including therapy-resistant forms. This cell death pathway may overcome resistance to targeted treatments.
Area of Science:
- Oncology
- Cell Biology
- Immunology
Background:
- Targeted and immune-based therapies for melanoma face limitations due to lack of response and acquired resistance.
- Pyroptosis, an inflammatory cell death, involves gasdermin (GSDM) pores releasing damage-associated molecular patterns (DAMPs) and cytokines.
- Inducing pyroptosis offers potential therapeutic strategies for both responsive and resistant melanoma.
Purpose of the Study:
- To investigate the potential of raptinal, a caspase-3 activator, in inducing pyroptosis in melanoma.
- To evaluate raptinal's efficacy in both therapy-naïve and treatment-resistant melanoma models.
- To assess the role of caspase activity and GSDME expression in raptinal-induced pyroptosis.
Main Methods:
- Utilized human and mouse melanoma cell line models.
- Administered raptinal to induce pyroptosis.
- Assessed tumor growth delay in vivo.
- Measured release of DAMPs and inflammatory cytokines.
- Investigated pyroptosis induction in melanoma models resistant to BRAF and MEK inhibitors.
Main Results:
- Raptinal effectively induced pyroptosis in both human and mouse melanoma cell lines.
- Raptinal treatment led to a delay in tumor growth in vivo.
- The release of DAMPs and cytokines was dependent on caspase activity and GSDME expression.
- Raptinal induced pyroptosis in melanoma models that had acquired resistance to BRAF and MEK inhibitor therapy.
Conclusions:
- Raptinal is a potent inducer of pyroptosis in melanoma, applicable to both treatment-naïve and resistant settings.
- The findings support the therapeutic potential of inducing pyroptosis to overcome resistance to targeted therapies in melanoma.
- Raptinal's ability to induce pyroptosis in resistant melanoma offers a promising avenue for future treatment strategies.
