AURORA, CO – Patients with melanoma who are refractory to or ineligible for immune checkpoint blockade have an urgent need for effective treatments.

A report in the journal Cancers (Basel) noted that includes patients who lack BRAF-V600E/K mutations and is often the situation with patients diagnosed with rare melanoma subtypes such as mucosal and acral melanoma.1

“Here, we 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,” wrote authors from University of Colorado Anschutz Medical Campus and the Denver VAMC. “Our data indicated higher B-cell CLL/lymphoma 2 (BCL2) expression in melanoma without BRAF hotspot mutations, suggesting that BH3 mimetics, such as ABT-199 (venetoclax, a small molecule against BCL2), may be a potential therapeutic option for these patients.”

Researchers said they 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.

The study advised that its data indicated that the 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”

The authors said their knockdown/knockout experiments suggested that several pro-apoptotic BCL2 family members, BCL2-like 11 (apoptosis facilitator) (BIM), phorbol-12-myristate-13-acetate-induced protein 1 (NOXA) or BID, might play a role in the combination-induced effects.

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

“Treatment options for patients with advanced cutaneous melanoma expanded significantly with FDA approval of immune-checkpoint blockade drugs and BRAF/MEK targeting signal transduction inhibitors,” the researchers emphasized. “Patients with metastatic or unresectable melanoma treated with combination immune checkpoint blockade (Ipilimumab/Nivolumab) or BRAF/MEK inhibition demonstrate 5-year overall survival of 52% and 34%, respectively. Despite these advances, a large proportion of patients treated with these medications will progress or not be eligible for targeted therapy.

“This includes those with BRAF-WT melanoma, and those who do not respond to immunotherapies. In addition, patients with rare melanoma subtypes, such as acral and mucosal, are genetically distinct from cutaneous melanomas and typically lack BRAF-V600E/K mutations, making them ineligible for BRAF/MEK inhibition. A large proportion of these patients (30–60%) also do not respond to immunotherapies.”

As a result, researchers noted the significant need to develop new treatments for those patients, adding, “Our study strongly suggests that combinations of BH3 mimetics that target both MCL1 and BCL2 may fill this role.”

  1. Mukherjee N, Amato CM, Skees J, Todd KJ, et. Al. Simultaneously Inhibiting BCL2 and MCL1 Is a Therapeutic Option for Patients with Advanced Melanoma. Cancers (Basel). 2020 Aug 5;12(8):2182. doi: 10.3390/cancers12082182. PMID: 32764384; PMCID: PMC7464298.