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

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  • Junfang Lyu

    (University of Macau, Avenida da Universidade, Taipa)

  • Eun Ju Yang

    (University of Macau, Avenida da Universidade, Taipa)

  • Baoyuan Zhang

    (University of Macau, Avenida da Universidade, Taipa)

  • Changjie Wu

    (University of Macau, Avenida da Universidade, Taipa)

  • Lakhansing Pardeshi

    (University of Macau, Avenida da Universidade, Taipa)

  • Changxiang Shi

    (University of Macau, Avenida da Universidade, Taipa)

  • Pui Kei Mou

    (University of Macau, Avenida da Universidade, Taipa)

  • Yifan Liu

    (University of Macau, Avenida da Universidade, Taipa)

  • Kaeling Tan

    (University of Macau, Avenida da Universidade, Taipa)

  • Joong Sup Shim

    (University of Macau, Avenida da Universidade, Taipa)

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.

Suggested Citation

  • Junfang Lyu & Eun Ju Yang & Baoyuan Zhang & Changjie Wu & Lakhansing Pardeshi & Changxiang Shi & Pui Kei Mou & Yifan Liu & Kaeling Tan & Joong Sup Shim, 2020. "Synthetic lethality of RB1 and aurora A is driven by stathmin-mediated disruption of microtubule dynamics," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18872-0
    DOI: 10.1038/s41467-020-18872-0
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