Synthetic lethality of RB1 and aurora A is driven by stathmin-mediated disruption of microtubule dynamics.

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 c

SUBMITTER: Lyu J 

PROVIDER: S-EPMC7547687 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature