Simultaneously Inhibiting BCL2 and MCL1 Is a Therapeutic Option for Patients with Advanced Melanoma

Abstract

There is an 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. This is often the case in patients diagnosed with rare melanoma subtypes such as mucosal and acral melanoma. 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. 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. We 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. 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. Overall, our study supports the rationale for combining an MCL1 inhibitor with a BCL2 inhibitor as a therapeutic option in patients with advanced melanoma.

Co-Operativity between MYC and BCL-2 Pro-Survival Proteins in Cancer

“…However, it is unclear whether such a strategy would ever be suitable for use in humans due to the potential risks involved. Notably, combinations targeting both MCL-1 and BCL-2 (e.g., S63845 and Venetoclax) have proven efficacious and safe in clinical trials in both haematological (e.g., AML, T-cell ALL, MCL) and solid cancers (e.g., melanoma) [252]. midline carcinoma, lung, breast, colon, prostate, brain etc) [285].…”

Targeting MCL-1 in cancer: current status and perspectives

“…MCL-1 depletion significantly induced apoptosis in melanoma cells and resensitized mutant BRAF melanoma cells to anoikis compared with depletion of BCL-2 or BCL-xL [ 148 ]. Combined inhibition of MCL-1 and BCL-xL by S63845/S64315 plus Navitoclax [ 149 ] or the combination of MCL-1 and BCL-2 by S63845/S64315 plus ABT-199 [ 150 ] synergistically induces extensive death in advanced/refractory melanoma cell lines both in vitro and in vivo. MIM1 promotes mitochondrial membrane rupture, glutathione depletion and cell cycle arrest, inducing melanoma cell death [ 151 , 152 ].…”

A Novel Regimen for Treating Melanoma: MCL1 Inhibitors and Azacitidine

“…The primary sphere assay measures the impact of a drug treatment on the viability of CSCs, including MICs. This technique hinges upon the ability of CSCs to survive and form spheres in nonadherent, serum-free conditions [ 19 , 23 , 24 , 25 , 26 ]. We examined the effect of combination treatment with S63845 + AZA on sphere formation using two representative melanoma cell lines, with mid-range sensitivity to combination treatment (SKMEL-28, MB3616) ( Figure 6 A,B).…”

“…Previously, expression of pro-apoptotic BCL2 family members (BIM and NOXA) have been identified as important for killing effects of combinations with BH3 mimetics in melanoma [ 23 ]. However, knockdown of either BIM or NOXA did not show consistent alteration of sensitivity to the combination treatment of MCL1i plus AZA, indicating that these proteins may not play a major role in sensitivity to this treatment ( Figure S4B ).…”

“…BH3 mimetics antagonize the action of anti-apoptotic proteins such as BCL2, MCL1 etc. Previous studies by our group and others indicate that combination treatments targeting BCL2 family proteins, particularly MCL1, may be a promising option in melanoma [ 17 , 19 , 23 ]. The combination treatment of AZA plus ABT-199 was recently approved for the treatment of some leukemias.…”