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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.
Highlights
RB1 mutational inactivation is a cancer driver in various types of cancer including lung cancer, making it an important target for therapeutic exploitation
There was no significant difference in cell proliferation rate between RB1+/+ and RB1−/− cell pairs (Supplementary Fig. 2a, b)
This study identified the hyper-vulnerability of RB1-deficient cells to aurora kinase A (AURKA) inhibition, and mechanistically explored the synthetic lethal crosstalk between RB1 and AURKA pathways in lung cancer cells
Summary
RB1 mutational inactivation is a cancer driver in various types of cancer including lung cancer, making it an important target for therapeutic exploitation. Aurora kinase A (AURKA) is a serine/threonine kinase whose activity peaks during G2/M transition in the cell cycle[9] It interacts with and phosphorylates a number of target proteins during the mitotic spindle assembly, centrosome separation, and cytokinesis, playing a critical role in mitosis[10]. A number of recent studies demonstrated that AURKA is frequently overexpressed in a wide spectrum of cancers[11,12,13,14,15,16], and its overexpression is associated with poor clinical outcomes in cancer patients[17,18], rendering it a highly important cancer target It has been identified as a synthetic lethal target for several tumor suppressors, including ARID1A19, SNF520, and SMARCA421, as well as RB1 very recently[22]. We suggest that upstream factors regulating microtubule dynamics are promising drug targets in lung cancer cells with RB1 loss-of-function mutations
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