AURORA, CO – Noting the urgent need to develop treatments for patients with melanoma who are refractory to or ineligible for immune checkpoint blockade, including patients who lack BRAF-V600E/K mutations, a new study suggested some possible options.

The report in Cancers (Basel) said the situation described above is often the case in patients diagnosed with rare melanoma subtypes such as mucosal and acral melanoma.1

Researchers from the University of Colorado Anschutz Medical Campus and the Denver VAMC analyzed data from the cutaneous melanoma The Cancer Genome Atlas Network (TCGA) transcriptomic and proteomic databases for differential expression of apoptosis molecules between melanomas with or without BRAF hotspot mutations.

The authors reported that their data indicated higher B-cell CLL/lymphoma 2 (BCL2) expression in melanoma without BRAF hotspot mutations; that suggested that BH3 mimetics, such as ABT-199 — venetoclax, a small molecule against BCL2 – could be a potential therapeutic option for those patients.

The study team explored the efficacy of combining two BH3 mimetics, ABT-199 and a myeloid cell leukemia sequence 1 (MCL1) inhibitor (S63845 or S64315/MIK665) in cutaneous, mucosal and acral melanomas, in vitro and in vivo.

“Our data indicate this combination induced cell death in a broad range of melanoma cell lines, including melanoma initiating cell populations, and was more potent in melanoma cells without BRAF-V600E/K mutations,” they wrote. “Our knockdown/knockout experiments suggest that several pro-apoptotic BCL2 family members, BCL2-like 11 (apoptosis facilitator) (BIM), phorbol-12-myristate-13-acetate-induced protein 1 (NOXA) or BID, play a role in the combination-induced effects.”

Researchers concluded that, overall, their study “supports the rationale for combining an MCL1 inhibitor with a BCL2 inhibitor as a therapeutic option in patients with advanced melanoma.”

  1. Mukherjee N, Amato CM, Skees J, et al. Simultaneously Inhibiting BCL2 and MCL1 Is a Therapeutic Option for Patients with Advanced Melanoma. Cancers (Basel). 2020;12(8):E2182. Published 2020 Aug 5. doi:10.3390/cancers12082182