Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau, SAR, China.
Nat Commun. 2020 Oct 9;11(1):5105. doi: 10.1038/s41467-020-18872-0.
RB1 mutational inactivation is a cancer driver in various types of cancer including lung cancer, making it an important target for therapeutic exploitation. We performed chemical and genetic vulnerability screens in RB1-isogenic lung cancer pair and herein report that aurora kinase A (AURKA) inhibition is synthetic lethal in RB1-deficient lung cancer. Mechanistically, RB1 cells show unbalanced microtubule dynamics through E2F-mediated upregulation of the microtubule destabilizer stathmin and are hypersensitive to agents targeting microtubule stability. Inhibition of AURKA activity activates stathmin function via reduced phosphorylation and facilitates microtubule destabilization in RB1 cells, heavily impacting the bipolar spindle formation and inducing mitotic cell death selectively in RB1 cells. This study shows that stathmin-mediated disruption of microtubule dynamics is critical to induce synthetic lethality in RB1-deficient cancer and suggests that upstream factors regulating microtubule dynamics, such as AURKA, can be potential therapeutic targets in RB1-deficient cancer.
RB1 基因突变失活是包括肺癌在内的多种癌症的驱动因素，使其成为治疗开发的重要靶点。我们在 RB1 同基因肺癌对中进行了化学和遗传易损性筛选，在此报告说，极光激酶 A（AURKA）抑制在 RB1 缺陷型肺癌中是合成致死的。从机制上讲，RB1 细胞通过 E2F 介导的微管不稳定蛋白 stathmin 的上调显示出不平衡的微管动力学，并且对靶向微管稳定性的药物高度敏感。AURKA 活性的抑制通过减少磷酸化激活 stathmin 的功能，并促进 RB1 细胞中的微管去稳定化，严重影响双极纺锤体的形成，并选择性地诱导 RB1 细胞中的有丝分裂细胞死亡。这项研究表明，stathmin 介导的微管动力学破坏对于诱导 RB1 缺陷型癌症中的合成致死性至关重要，并表明调节微管动力学的上游因素，如 AURKA，可能是 RB1 缺陷型癌症的潜在治疗靶点。
