Triple-negative breast cancer (TNBC) is an aggressive cancer that lacks specific molecular targets that are often used for therapy. The refractory rate of TNBC to broad-spectrum chemotherapy remains high; however, the combination of newly developed treatments with the current standard of care has delivered promising anti-tumor effects. One mechanism employed by TNBC to avoid cell death is the increased expression of the anti-apoptotic protein, myeloid cell leukemia 1 (MCL1). Multiple studies have demonstrated that increased MCL1 expression enables resistance to platinum-based chemotherapy. In addition to suppressing apoptosis, we recently demonstrated that MCL1 also binds and negatively regulates the transcriptional activity of TP73. TP73 upregulation is a critical driver of cisplatin-induced DNA damage response, and ultimately, cell death. We therefore sought to determine if the coadministration of an MCL1-targeted inhibitor with cisplatin could produce a synergistic response in TNBC. This study demonstrates that the MCL1 inhibitor, S63845, combined with cisplatin synergizes by inducing apoptosis while also decreasing proliferation in a subset of TNBC cell lines. The use of combined MCL1 inhibitors with cisplatin in TNBC effectively initiates TAp73 anti-tumor effects on cell cycle arrest and apoptosis. This observation provides a molecular profile that can be exploited to identify sensitive TNBCs.
三阴性乳腺癌是一种侵袭性癌症，缺乏常用于治疗的特定分子靶点。尽管其对广谱化疗的耐药率仍然较高，但新开发的治疗方法与当前标准护理相结合已展现出良好的抗肿瘤效果。三阴性乳腺癌避免细胞死亡的一种机制是抗凋亡蛋白髓样细胞白血病1（MCL1）的表达增加。多项研究表明，MCL1表达增加会导致对铂类化疗药物的耐药性。除了抑制细胞凋亡外，我们最近还发现MCL1能够结合并负调控TP73的转录活性。TP73上调是顺铂诱导DNA损伤反应并最终导致细胞死亡的关键驱动因素。因此，我们试图确定MCL1靶向抑制剂与顺铂联合使用是否能在三阴性乳腺癌中产生协同效应。本研究表明，MCL1抑制剂S63845与顺铂联合使用时，通过诱导细胞凋亡并在部分三阴性乳腺癌细胞系中降低增殖能力，产生协同作用。在三阴性乳腺癌中联合使用MCL1抑制剂与顺铂，能有效启动TAp73对细胞周期阻滞和细胞凋亡的抗肿瘤效应。这一发现为识别敏感的三阴性乳腺癌提供了可利用的分子特征谱。
肿瘤(癌症)患者之家