Duan Lei, Maki Carl G
Department of Anatomy and Cell Biology, Rush University Medical Center, Chicago, IL 60612, USA.
Cell Signal (Middlet). 2024;2(1):144-147. doi: 10.46439/signaling.2.046.
MCL1 is an anti-apoptotic member of the BCL2 protein family, and its overexpression is associated with poor prognosis across various cancers. Small molecule inhibitors targeting MCL1 are currently in clinical trials for TNBC and other malignancies. However, one major challenge in the clinical application of MCL1 inhibitors is the inherent or acquired resistance to these drugs. Additionally, there is a lack of predictive biomarkers to identify which tumors will respond to MCL1 inhibition. We identified a four-gene functional signature that promotes MCL1 inhibitor resistance in TNBC cells. This gene signature (GS) can distinguish resistant from sensitive TNBC cell lines. Factors encoded by these four genes promote MCL1 inhibitor resistance at least in part through regulation of the ERK signaling pathway. This mechanism involves the upregulation of BCL2 and the downregulation of BIM, which contribute to the inhibitor resistance. Thus, we have discovered a functional GS that drives MCL1 inhibitor resistance. Currently, the MCL1 inhibitor GS-9716 is in clinical trials for TNBC therapy. If validated in clinical samples, this GS could potentially serve as a predictive biomarker for therapy response and help guide the selection of combination therapies to enhance the effectiveness of MCL1 inhibitors.
MCL1是BCL2蛋白家族的一个抗凋亡成员，其过表达与多种癌症的不良预后相关。靶向MCL1的小分子抑制剂目前正在用于三阴性乳腺癌（TNBC）和其他恶性肿瘤的临床试验。然而，MCL1抑制剂临床应用中的一个主要挑战是对这些药物的固有或获得性耐药。此外，缺乏预测性生物标志物来识别哪些肿瘤会对MCL1抑制产生反应。我们鉴定出了一个促进TNBC细胞对MCL1抑制剂耐药的四基因功能特征。这个基因特征（GS）可以区分耐药和敏感的TNBC细胞系。这四个基因编码的因子至少部分通过调节ERK信号通路促进MCL1抑制剂耐药。这种机制涉及BCL2的上调和BIM的下调，这有助于产生抑制剂耐药。因此，我们发现了一种驱动MCL1抑制剂耐药的功能性GS。目前，MCL1抑制剂GS-9716正在用于TNBC治疗的临床试验。如果在临床样本中得到验证，这个GS可能会作为治疗反应的预测性生物标志物，并有助于指导联合治疗的选择以提高MCL1抑制剂的有效性。
