MCL1 inhibitors S63845/MIK665 plus Navitoclax synergistically kill difficult-to-treat melanoma cells
MCL1 inhibitors S63845/MIK665 plus Navitoclax synergistically kill difficult-to-treat melanoma cells
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DOI：
10.1038/s41419-020-2646-2
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发表时间：
2020-06-08
影响因子：
9
通讯作者：
Shellman, Yiqun G.
中科院分区：
文献类型：
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作者：
Mukherjee, Nabanita;Skees, Jenette;Shellman, Yiqun G.
目前对转移性黑色素瘤患者的治疗包括分子靶向治疗和免疫检查点抑制剂。然而，黑色素瘤的一个子集是难以治疗的。这些黑色素瘤包括那些没有靶向治疗的遗传标记，对免疫治疗无反应，以及那些复发或用尽治疗选择的黑色素瘤。因此，有必要了解和探索可能提供新的治疗方法的其他生物学过程。其中最吸引人的是靶向对白血病有效的凋亡/抗凋亡系统。我们使用BH 3模拟物的遗传敲除和药理学方法来靶向抗凋亡BCL 2家族成员，并将MCL 1和BCL XL鉴定为黑色素瘤中关键的促存活成员。然后，我们在体外和体内检查了将BH 3模拟物组合以靶向MCL 1和BCLXL的效果。这些包括临床试验准备的化合物，如ABT-263（Navitoclax）和S63845/S64315（MIK 655）。我们使用了来自难治性黑色素瘤患者的细胞系。在体外，在多个测定（包括球体测定）中，与单一药剂处理相比，MCL 1和BCLXL的组合抑制导致显著有效的细胞杀伤（p < 0.05）。组合诱导的细胞死亡不依赖于BIM和NOXA。在我们的小鼠异种移植模型中，该组合抑制肿瘤生长，降低球体形成能力（分别为p < 0.01和0.05），并且具有可耐受的毒性（p > 0.40）。总之，这项研究表明，MCL 1和BCLXL的双重靶向治疗应被视为难治性黑色素瘤患者的治疗选择。
Current treatment for patients with metastatic melanoma include molecular-targeted therapies and immune checkpoint inhibitors. However, a subset of melanomas are difficult-to-treat. These melanomas include those without the genetic markers for targeted therapy, non-responsive to immunotherapy, and those who have relapsed or exhausted their therapeutic options. Therefore, it is necessary to understand and explore other biological processes that may provide new therapeutic approaches. One of most appealing is targeting the apoptotic/anti-apoptotic system that is effective against leukemia. We used genetic knockdown and pharmacologic approaches of BH3 mimetics to target anti-apoptotic BCL2 family members and identified MCL1 and BCLXL as crucial pro-survival members in melanoma. We then examined the effects of combining BH3 mimetics to target MCL1 and BCLXL in vitro and in vivo. These include clinical-trial-ready compounds such as ABT-263 (Navitoclax) and S63845/S64315 (MIK655). We used cell lines derived from patients with difficult-to-treat melanomas. In vitro, the combined inhibition of MCL1 and BCLXL resulted in significantly effective cell killing compared to single-agent treatment (p < 0.05) in multiple assays, including sphere assays. The combination-induced cell death was independent of BIM, and NOXA. Recapitulated in our mouse xenograft model, the combination inhibited tumor growth, reduced sphere-forming capacity (p < 0.01 and 0.05, respectively), and had tolerable toxicity (p > 0.40). Taken together, this study suggests that dual targeting of MCL1 and BCLXL should be considered as a treatment option for difficult-to-treat melanoma patients.