Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio.
Department of Pathology, School of Medicine, New York University, New York, New York.
Cancer Res. 2020 Apr 15;80(8):1693-1706. doi: 10.1158/0008-5472.CAN-19-3466. Epub 2020 Feb 13.
A significant therapeutic challenge for patients with cancer is resistance to chemotherapies such as taxanes. Overexpression of LIN9, a transcriptional regulator of cell-cycle progression, occurs in 65% of patients with triple-negative breast cancer (TNBC), a disease commonly treated with these drugs. Here, we report that LIN9 is further elevated with acquisition of taxane resistance. Inhibiting LIN9 genetically or by suppressing its expression with a global BET inhibitor restored taxane sensitivity by inducing mitotic progression errors and apoptosis. While sustained LIN9 is necessary to maintain taxane resistance, there are no inhibitors that directly repress its function. Hence, we sought to discover a druggable downstream transcriptional target of LIN9. Using a computational approach, we identified NIMA-related kinase 2 (NEK2), a regulator of centrosome separation that is also elevated in taxane-resistant cells. High expression of was predictive of low survival rates in patients who had residual disease following treatment with taxanes plus an anthracycline, suggesting a role for this kinase in modulating taxane sensitivity. Like LIN9, genetic or pharmacologic blockade of NEK2 activity in the presence of paclitaxel synergistically induced mitotic abnormalities in nearly 100% of cells and completely restored sensitivity to paclitaxel, . In addition, suppressing NEK2 activity with two distinct small molecules potentiated taxane response in multiple models of TNBC, including a patient-derived xenograft, without inducing toxicity. These data demonstrate that the LIN9/NEK2 pathway is a therapeutically targetable mediator of taxane resistance that can be leveraged to improve response to this core chemotherapy. SIGNIFICANCE: Resistance to chemotherapy is a major hurdle for treating patients with cancer. Combining NEK2 inhibitors with taxanes may be a viable approach for improving patient outcomes by enhancing mitotic defects induced by taxanes alone.
对于癌症患者来说，一个重大的治疗挑战是对化疗药物（如紫杉醇）产生耐药性。在三阴性乳腺癌（TNBC）患者中，有 65%存在细胞周期进程转录调节剂 LIN9 的过表达，这种疾病通常用这些药物治疗。在这里，我们报告说，随着对紫杉醇耐药性的获得，LIN9 的表达进一步升高。通过基因抑制 LIN9 或用全局 BET 抑制剂抑制其表达，通过诱导有丝分裂进展错误和细胞凋亡，恢复了对紫杉醇的敏感性。虽然持续的 LIN9 是维持紫杉醇耐药性所必需的，但没有直接抑制其功能的抑制剂。因此，我们试图发现 LIN9 的可用药的下游转录靶标。使用计算方法，我们鉴定了 NIMA 相关激酶 2（NEK2），一种中心体分离的调节剂，在紫杉醇耐药细胞中也被上调。在接受紫杉醇加蒽环类药物治疗后仍有残留疾病的患者中，高表达与生存率降低相关，这表明该激酶在调节紫杉醇敏感性方面发挥作用。与 LIN9 一样，在紫杉醇存在的情况下，通过基因或药物抑制 NEK2 活性可协同诱导近 100%的细胞有丝分裂异常，并完全恢复对紫杉醇的敏感性。此外，用两种不同的小分子抑制 NEK2 活性可增强多种 TNBC 模型（包括患者来源的异种移植物）对紫杉醇的反应，而不会引起毒性。这些数据表明，LIN9/NEK2 途径是一种有治疗潜力的紫杉醇耐药性介导因子，可用于提高对这种核心化疗药物的反应。意义：对化疗药物的耐药性是治疗癌症患者的主要障碍。联合 NEK2 抑制剂和紫杉醇可能是一种可行的方法，可以通过增强紫杉醇单独诱导的有丝分裂缺陷来改善患者的结局。
