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Preclinical Study Explores BH3 Mimetic Combinations in Melanoma

By: Sarah Campen, PharmD
Posted: Thursday, January 16, 2020

Research presented at the 2019 International Congress of The Society for Melanoma Research (SMR) in Salt Lake City suggests that targeting the antiapoptotic proteins MCL1 and BCLXL with BCL-2 homology domain-3 (BH3) mimetics may be a “promising” treatment option for melanoma. Nabanita Mukherjee, PhD, of the University of Colorado in Aurora, and colleagues discovered that combining two BH3 mimetics effectively debulked and killed melanoma-initiating cells in vitro and significantly inhibited tumor growth in mouse models compared with one BH3 mimetic alone.

The researchers tested doublet combinations of three different BH3 mimetics, revealing that S63845 (MCL1-i) plus either ABT263 (BCL2/BCLXL/BCLW-i) or A1331852 (BCLXL-i) appear to have therapeutic potential. Both combinations efficiently debulked and killed melanoma-initiating cells—including those resistant to targeted and/or anti–PD-1 therapy—better than single drugs (P < .05).

The BH3 mimetic combinations also inhibited tumor growth compared with a single agent (P < .01) in mouse xenograft models. Tumor cells isolated from these mice had significantly lower sphere-forming capacity when treated with the combination treatments than with a single BH3 mimetic, “supporting the idea that the combinations kill melanoma-initiating cells.”

Disclosure: For full disclosures of the study authors, visit societymelanomaresearch.org/congress.



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