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A Novel Regimen for Treating Melanoma: MCL1 Inhibitors and Azacitidine
Chiara R Dart1,2, Nabanita Mukherjee1, Carol M Amato2
1Department of Dermatology, School of Medicine, University of Colorado Anschutz Medical Campus, Mail Stop 8127, Aurora, CO 80045, USA.
Abstract:
Although treatment options for melanoma patients have expanded in recent years with the approval of immunotherapy and targeted therapy, there is still an unmet need for new treatment options for patients that are ineligible for, or resistant to these therapies. BH3 mimetics, drugs that mimic the activity of pro-apoptotic BCL2 family proteins, have recently achieved remarkable success in the clinical setting. The combination of BH3 mimetic ABT-199 (venetoclax) plus azacitidine has shown substantial benefit in treating acute myelogenous leukemia. We evaluated the efficacy of various combinations of BH3 mimetic + azacitidine in fourteen human melanoma cell lines from cutaneous, mucosal, acral and uveal subtypes. Using a combination of cell viability assay, BCL2 family knockdown cell lines, live cell imaging, and sphere formation assay, we found that combining inhibition of MCL1, an anti-apoptotic BCL2 protein, with azacitidine had substantial pro-apoptotic effects in multiple melanoma cell lines. Specifically, this combination reduced cell viability, proliferation, sphere formation, and induced apoptosis. In addition, this combination is highly effective at reducing cell viability in rare mucosal and uveal subtypes. Overall, our data suggest this combination as a promising therapeutic option for some patients with melanoma and should be further explored in clinical trials.
Insights
Combining MCL1 inhibitors with azacitidine shows promise for melanoma treatment. This approach targets cancer cell death and is effective even in rare melanoma subtypes, offering new therapeutic options.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Melanoma treatment options are expanding, but resistance and ineligibility for current therapies necessitate novel approaches.
- BH3 mimetics, which mimic pro-apoptotic BCL2 proteins, have shown clinical success.
- The combination of venetoclax (ABT-199) and azacitidine is effective in acute myelogenous leukemia.
Purpose of the Study:
- To evaluate the efficacy of combining BH3 mimetics with azacitidine in various human melanoma subtypes.
- To identify specific BCL2 family protein targets that enhance azacitidine's anti-melanoma effects.
Main Methods:
- Utilized fourteen human melanoma cell lines (cutaneous, mucosal, acral, uveal).
- Employed cell viability assays, BCL2 family knockdown models, live cell imaging, and sphere formation assays.
- Investigated combinations of BH3 mimetics with azacitidine.
Main Results:
- Combining MCL1 inhibition with azacitidine demonstrated significant pro-apoptotic effects across multiple melanoma cell lines.
- This combination reduced cell viability, proliferation, and sphere formation, while inducing apoptosis.
- The combination proved highly effective in reducing cell viability in rare mucosal and uveal melanoma subtypes.
Conclusions:
- The combination of MCL1 inhibition and azacitidine is a promising therapeutic strategy for melanoma.
- This approach warrants further investigation in clinical trials, particularly for patients with limited treatment options.
- The findings highlight potential for treating rare melanoma subtypes effectively.
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