Global Drug Discovery, Therapeutic Research Group Oncology, Bayer Healthcare Pharmaceuticals Berlin, Germany.
Front Oncol. 2011 Nov 16;1:44. doi: 10.3389/fonc.2011.00044. eCollection 2011.
Sagopilone, a fully synthetic epothilone, is a microtubule-stabilizing agent optimized for high in vitro and in vivo activity against a broad range of tumor models, including those resistant to paclitaxel and other systemic treatments. Sagopilone development is accompanied by translational research studies to evaluate the molecular mode of action, to recognize mechanisms leading to resistance, to identify predictive response biomarkers, and to establish a rationale for combination with different therapies. Here, we profiled sagopilone activity in breast cancer cell lines. To analyze the mechanisms of mitotic arrest and apoptosis and to identify additional targets and biomarkers, an siRNA-based RNAi drug modifier screen interrogating 300 genes was performed in four cancer cell lines. Defects of the spindle assembly checkpoint (SAC) were identified to cause resistance against sagopilone-induced mitotic arrest and apoptosis. Potential biomarkers for resistance could therefore be functional defects like polymorphisms or mutations in the SAC, particularly in the central SAC kinase BUB1B. Moreover, chromosomal heterogeneity and polyploidy are also potential biomarkers of sagopilone resistance since they imply an increased tolerance for aberrant mitosis. RNAi screening further demonstrated that the sagopilone-induced mitotic arrest can be enhanced by concomitant inhibition of mitotic kinesins, thus suggesting a potential combination therapy of sagopilone with a KIF2C (MCAK) kinesin inhibitor. However, the combination of sagopilone and inhibition of the prophase kinesin KIF11 (EG5) is antagonistic, indicating that the kinesin inhibitor has to be highly specific to bring about the required therapeutic benefit.
沙格列汀，一种完全合成的埃坡霉素，是一种微管稳定剂，具有针对广泛肿瘤模型的高体外和体内活性，包括对紫杉醇和其他全身治疗耐药的模型。沙格列汀的开发伴随着转化研究，以评估其分子作用模式，识别导致耐药的机制，确定预测反应的生物标志物，并为与不同疗法的联合治疗建立合理的依据。在这里，我们研究了沙格列汀在乳腺癌细胞系中的活性。为了分析有丝分裂阻滞和细胞凋亡的机制，并确定其他靶点和生物标志物，我们在四种癌细胞系中进行了基于 siRNA 的 RNAi 药物修饰筛选，共检测了 300 个基因。发现纺锤体装配检查点（SAC）缺陷导致对沙格列汀诱导的有丝分裂阻滞和凋亡产生耐药性。因此，潜在的耐药生物标志物可能是 SAC 的功能缺陷，如多态性或突变，特别是在中央 SAC 激酶 BUB1B 中。此外，染色体异质性和多倍体也是沙格列汀耐药的潜在生物标志物，因为它们意味着对异常有丝分裂的耐受性增加。RNAi 筛选还表明，同时抑制有丝分裂驱动蛋白可以增强沙格列汀诱导的有丝分裂阻滞，因此提示沙格列汀与有丝分裂驱动蛋白 KIF2C（MCAK）抑制剂联合治疗的潜在组合疗法。然而，沙格列汀与前期驱动蛋白 KIF11（EG5）抑制剂的联合使用具有拮抗作用，这表明该驱动蛋白抑制剂必须具有高度特异性才能带来所需的治疗益处。
