文章：

MCL-1抑制剂在曲美替尼耐药黑色素瘤细胞中的促凋亡活性取决于其表型，并受曲美替尼撤药诱导的可逆性改变调控

Pro-Apoptotic Activity of MCL-1 Inhibitor in Trametinib-Resistant Melanoma Cells Depends on Their Phenotypes and Is Modulated by Reversible Alterations Induced by Trametinib Withdrawal

原文发布日期：29 September 2023

DOI: 10.3390/cancers15194799

类型: Article

开放获取: 是

英文摘要：

Background: Although BRAFV600/MEK inhibitors improved the treatment of melanoma patients, resistance is acquired almost inevitably. Methods: Trametinib withdrawal/rechallenge and MCL-1 inhibition in trametinib-resistance models displaying distinct p-ERK1/2 levels were investigated. Results: Trametinib withdrawal/rechallenge caused reversible changes in ERK1/2 activity impacting the balance between pro-survival and pro-apoptotic proteins. Reversible alterations were found in MCL-1 levels and MCL-1 inhibitors, BIM and NOXA. Taking advantage of melanoma cell dependency on MCL-1 for survival, we used S63845. While it was designed to inhibit MCL-1 activity, we showed that it also significantly reduced NOXA levels. S63845-induced apoptosis was detected as the enhancement of Annexin V-positivity, caspase-3/7 activation and histone H2AX phosphorylation. Percentages of Annexin V-positive cells were increased most efficiently in trametinib-resistant melanoma cells displaying the p-ERK1/2low/MCL-1low/BIMhigh/NOXAlowphenotype with EC50values at concentrations as low as 0.1 μM. Higher ERK1/2 activity associated with increased MCL-1 level and reduced BIM level limited pro-apoptotic activity of S63845 further influenced by a NOXA level. Conclusions: Our study supports the notion that the efficiency of an agent designed to target a single protein can largely depend on the phenotype of cancer cells. Thus, it is important to define appropriate phenotype determinants to stratify the patients for the novel therapy.

摘要翻译： 

背景：尽管BRAFV600/MEK抑制剂改善了黑色素瘤患者的治疗效果，但耐药性的产生几乎不可避免。方法：本研究在具有不同p-ERK1/2表达水平的曲美替尼耐药模型中，考察了曲美替尼撤药/再给药方案及MCL-1抑制策略。结果：曲美替尼的撤药/再给药可引起ERK1/2活性的可逆性变化，从而影响促生存蛋白与促凋亡蛋白之间的平衡。在MCL-1水平及其抑制剂BIM、NOXA中均观察到可逆性改变。利用黑色素瘤细胞生存对MCL-1的依赖性，我们采用S63845开展研究。该药物虽设计用于抑制MCL-1活性，但本研究发现其还能显著降低NOXA水平。通过膜联蛋白V阳性率升高、caspase-3/7激活及组蛋白H2AX磷酸化等指标，检测到S63845诱导的细胞凋亡。在呈现p-ERK1/2低表达/MCL-1低表达/BIM高表达/NOXA低表达表型的曲美替尼耐药黑色素瘤细胞中，膜联蛋白V阳性细胞比例增加最为显著，其半数有效浓度值低至0.1 μM。较高的ERK1/2活性伴随MCL-1水平升高和BIM水平降低，限制了S63845的促凋亡活性，而NOXA水平对此过程产生进一步影响。结论：本研究证实，针对单一蛋白设计的药物疗效在很大程度上取决于癌细胞的表型特征。因此，明确合适的表型决定因素对患者进行新型疗法分层至关重要。

原文链接：

Pro-Apoptotic Activity of MCL-1 Inhibitor in Trametinib-Resistant Melanoma Cells Depends on Their Phenotypes and Is Modulated by Reversible Alterations Induced by Trametinib Withdrawal