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

Nabanita Mukherjee,Chiara R Dart,Carol M Amato,Ryan M Weight,Kaleb J Todd,David A Norris,Richard P Tobin,Martin D Mccarter,Robert Van Gulick,Yiqun G Shellman,Mayumi Fujita,Karoline A Lambert,Jenette Skees,William A Robinson

doi:10.3390/cancers12082182

Nabanita Mukherjee, Chiara R Dart + Show 12 more

Open Access

https://doi.org/10.3390/cancers12082182

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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.

Highlights

BH3 mimetics are a novel class of anti-cancer drugs that mimic the action of certain BH3-only anti-apoptotic proteins of the B-cell CLL/lymphoma 2 (BCL2) family, which directly initiate apoptosis, downstream of many common oncogenes [1,2,3,4]
Considering that higher BCL2 levels are associated with sensitivity to ABT-199 in other cancers [12,13,14], these data provide a rationale for testing the efficacy of BCL2 inhibitors, such as ABT-199, in patients with BRAF-WT melanomas
A sub-population of cells has enhanced plasticity, drug resistance and stem-cell-like features. These cells are referred to as Melanoma Initiating Cells (MICs) and may contribute to healthy overall during regular monitoring throughout the duration of the studies. These results collectively indicate that the combination of the myeloid cell leukemia sequence 1 (MCL1) inhibitors with the BCL2 inhibitor ABT-199 is effective in killing advanced melanomas

Summary

Introduction

BH3 mimetics are a novel class of anti-cancer drugs that mimic the action of certain BH3-only anti-apoptotic proteins of the B-cell CLL/lymphoma 2 (BCL2) family, which directly initiate apoptosis, downstream of many common oncogenes [1,2,3,4]. In the last five years, the BH3 mimetic, ABT-199. Single agent BH3 mimetics have shown inconsistent efficacy in solid tumors [6,7]. ABT-199 is the only FDA-approved BH3 mimetic. Clinical trials using ABT-199 plus another anti-apoptotic member of the BCL2 family, a BH3 mimetic targeting myeloid cell leukemia sequence 1 (MCL1), are underway to extend the efficacy of ABT-199 in hematological malignancies. The use of these compounds in solid tumors is being investigated in the pre-clinical phase [5,8,9]

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