한빛사 논문
Junfang Lyu1, Eun Ju Yang1, Baoyuan Zhang1, Changjie Wu1, Lakhansing Pardeshi1, Changxiang Shi1, Pui Kei Mou1, Yifan Liu1, Kaeling Tan1 & Joong Sup Shim1,*
1Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau, SAR, China.
*Corresponding author
Abstract
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.
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